2-azaspiro[3.4]octane derivatives as m4 agonists

ABSTRACT

Provided herein are compounds according to Formula (I)or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R5, and R7 are defined herein. Also provided herein are pharmaceutical compositions comprising a compound of Formula (I) as well as the use of such compounds as M4 receptor agonists.

1. CROSS REFERENCE TO RELATED APPLICATIONS

This application is claims the benefit of priority to U.S. ProvisionalApplication No. 62/912,980, filed Oct. 9, 2019, the disclosure of whichis incorporated by reference herein in its entirety.

2. FIELD

Provided herein are novel 2-azaspiro[3.4]octane compounds that act as M4receptor agonists, as well as pharmaceutical compositions thereof, usesfor the treatment of conditions, diseases and disorders related to theM4 receptor, which include, but are not limited to, psychosis,hyperkinetic movement disorders, cognitive dysfunction, and substanceuse disorders.

3. BACKGROUND

Acetylcholine, a major neurotransmitter in the central and peripheralnervous system, signals by activating its ionotropic (nicotinic) andG-protein coupled (muscarinic) receptors. Five muscarinic receptors(M1-M5) have been identified with differential expression and signaling.The M1, M3 and M5 receptors are coupled to Gq proteins that activatephospholipase C. Phospholipase C hydrolyses membrane phosphoinositidesinto inositol triphosphate (IP₃) and diacylglycerol (DAG), which elevateintracellular calcium and activate a number of signaling pathways. TheM2 and M4 receptors are coupled to G_(i/o) proteins which inhibitadenylyl cyclase production and decrease cyclic adenosine monophosphate(cAMP) levels, having an inhibitory effect on cell function. The M1receptors are predominantly expressed in the forebrain (cortex,hippocampus, striatum and thalamus) and on salivary glands (Brain ResMol Brain Res 2005, 133(1):6-11; Br. J. Pharmacol 2006, 148, 565-578;Pharmacol Ther 2008, 117: 232-243). The M2 receptors are expressed inthe brain, and also highly expressed in the heart where they mediatevagal nerve innervation and can affect the heart rate (Br. J. Pharmacol2006, 148, 565-578; Pharmacol Ther 2008, 117: 232-243). The M3 receptorsare mostly expressed in the smooth muscles of peripheral tissues,including the gastrointestinal track, bladder, eye, and sweat andsalivary glands (Br. J. Pharmacol 2006, 148, 565-578). The M4 receptorsare enriched in the brain and are mainly expressed in the striatum, abrain area involved in dopamine release and signaling (J Neurosci 199414(5):3351-3363; Proc Natl Acad Sci USA 1999, 96(18): 10483-10488;Pharmacol Ther 2008, 117: 232-243). The M5 receptors are expressed onvasculature, including the cerebral blood vessels (Proc Natl Acad SciUSA 2001, 98(24):14096-14101).

In the central nervous system, muscarinic receptors have been shown toplay a central role in cognition and regulation of dopaminergicsignaling (Neuron 2017, 94(3): 431-446). Of particular interest are M4receptors that are highly expressed in the striatum. Genetic deletion ofM4 receptors causes a hyper-dopaminergic phenotype in rodents. M4knock-out mice have been shown to have elevated striatal dopamine levelsand increased locomotor activity (Proc Natl Acad Sci USA 1999, 96(18):10483-10488.; FASEB J 2004, 18(12):1410-1412). Consistent with theseobservations, pharmacological activation of M4 receptors decreasesamphetamine-induced dopamine release and reverses amphetaminehyperlocomotion in mice (Neuropsychopharm 2004, 39: 1578-1593). Thus,these results indicate that M4 receptors can act as a negative regulatorof dopamine release and signaling in the striatum.

Increased dopamine tone in the striatum is strongly associated withpsychotic symptoms in schizophrenia and other disorders, includingpsychotic depression, bipolar disorder, Huntington's disease andAlzheimer's disease (Lancet 1988, 2:119-125; Schizophr Bull 2009,35:549-562). Current antipsychotic drugs act primarily by blocking theaction of dopamine at D2 receptors. However, they have limited efficacyand serious side effects, including drug-induced Parkinsonism, tardivedyskinesia, Q-Tc prolongation, weight gain and metabolic syndrome whichlead to poor patient compliance (N Engl J Med 2005, 353:1209-23).

Activation of muscarinic M4 receptors has been shown to downregulatestriatal dopamine signaling and thereby may provide an alternative wayto treat psychosis. In support of this notion, the muscarinic agonistxanomeline showed robust antipsychotic efficacy when tested in twoclinical trials in Alzheimer disease (Arch Neurol 1997, 54(4):465-473)and schizophrenia patients (Am J Psychiatry 2008, 165(8):1033-1039).However, its treatment was associated with a number of side effects,including nausea, vomiting, excessive salivation, dyspepsia and chills,which stopped its clinical development. Xanomeline is a pan muscarinicagonist that activates all muscarinic receptor subtypes. Studies suggestthat the antipsychotic efficacy of xanomeline is primarily mediated bythe activation of M4 receptors. The M4 receptors are highly expressed inthe human striatum (Schizophr Res 2015, 169: 83-88.) and theantipsychotic-like effects of xanomeline on dopamine-mediated behaviorsare eliminated in M4 knock-out mice (Eur J Pharmacol 2009, 603: 147-149;J Neurosci 2011, 31(16):5905-5908.). In contrast, xanomeline's sideeffects are most likely due to the activation of M2 and M3 receptorswhich are expressed in the heart, digestive tract and salivary glands(CNS Drug Rev 2003, 9:159-186; Br. J. Pharmacol 2006, 148, 565-578).Thus, M4 selective agonists are likely to retain xanomeline'santipsychotic efficacy without causing cholinergic side effects.

Consequently, compounds that act as M4 receptor agonists may be usefulfor treatment of M4 related conditions.

4. SUMMARY

In one embodiment, provided herein is a compound according to Formula(I)

or a pharmaceutically acceptable salt thereof, wherein

R¹ is halogen or hydrogen;

R² is halogen or hydrogen;

R³ is

-   -   C₁₋₆ alkyl, said alkyl is optionally substituted with one or two        substituents independently selected from the group consisting of        4 to 6-membered heterocycloalkyl and —OH,    -   5 to 6-membered heteroaryl,    -   3 to 6-membered cycloalkyl, said cycloalkyl is optionally        substituted with one —OH,    -   5 to 6-membered heterocycloalkyl, said heterocycloalkyl is        optionally substituted with one —OH, or    -   —OR⁴;

R⁴ is

-   -   —CF₃,    -   —CF₂H,    -   C₁₋₆ alkyl, said alkyl is optionally substituted with one or two        R⁶,    -   3 to 6-membered cycloalkyl,    -   4 to 7-membered heterocycloalkyl, said heterocycloalkyl is        optionally substituted with one R⁶,    -   5 to 6-membered heteroaryl, or    -   R⁴ is one of the following groups:

R⁵ is halogen or hydrogen;

each R⁶ is independently

-   -   halogen,    -   —OH,    -   —CF₃,    -   —CF₂H,    -   cyano,    -   —OCF₃,    -   —OCH₃,    -   —O-heterocycloalkyl,    -   C₁-C₄ alkyl,    -   4 to 7-membered heterocycloalkyl, said heterocycloalkyl is        optionally substituted with one or two substituents        independently selected from the group consisting of halogen,        —OH, and C₁₋₃ alkyl,    -   5 to 6-membered heteroaryl, said heteroaryl is optionally        substituted with one or two C₁₋₃ alkyl,    -   3 to 6-membered cycloalkyl, said cycloalkyl is optionally        substituted with one —CF₃, or    -   each of R⁶ is independently one of the following groups:

R⁷ is

-   -   a 5 to 6-membered heteroaryl, said heteroaryl is optionally        substituted with one substituent selected from the group        consisting of C₁-C₆ alkyl, —CF₃, and halogen, or    -   C(O)R⁸; and

R⁸ is

-   -   3 to 6-membered cycloalkyl, said cycloalkyl is optionally        substituted with one halogen, or    -   4 to 6-membered heterocycloalkyl.

In one embodiment, provided herein is a compound according to Formula(Ia)

or a pharmaceutically acceptable salt or stereoisomer thereof.

In one embodiment, provided herein is a compound according to Formula(Ib)

or a pharmaceutically acceptable salt or stereoisomer thereof.

In one embodiment, R¹ is selected from the group consisting of H,chloro, and fluoro.

In one embodiment, R² is H or fluoro.

In one embodiment, R⁵ is H or fluoro.

In one embodiment, R¹, R², and R⁵ are H.

In one embodiment, R³ is selected from the group consisting of:

In another embodiment, R³ is —OR⁴.

In one embodiment, R⁴ is selected from the group consisting of —CH₃,—CF₃, —CF₂H, —CH₂CH₃, —CH(CH₃)₂, —CH₂CF₂H, —CH₂CH₂F, —(CH₂)₂CF₃,—CH₂C(CH₃)₂F, —(CH₂)₂OCF₃, —(CH₂)₂OH, —(CH₂)₂OCH₃, —CH₂C(CH₃)₂OH,—(CH₂)₂C(CH₃)₂OH, —(CH₂)₂C(CH₃)₂OCH₃, —CH₂C(CH₃)₂OCH₃, —(CH₂)₂CN, and—CH₂CH(CH₃)₂. In another embodiment, R⁴ is selected from the groupconsisting of:

In one embodiment, R⁷ is 5 to 6-membered heteroaryl or —C(O)R⁸. Inanother embodiment. R⁷ is

In other embodiments, R⁷ is —C(O)R⁸.

In one embodiment, R⁸ is 4 to 6-membered heterocycloalkyl or 3 to6-membered cycloalkyl. In another embodiment, R⁸ is 4 to 6-memberedheterocycloalkyl. In other preferred embodiments, R⁸ is

In certain embodiments, R⁸ is 3 to 6-membered cycloalkyl, said 3 to6-membered cycloalkyl is substituted with one halogen.

In one embodiment, provided herein is a compound selected from the groupconsisting of:

-   (R)-2-(6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole;-   (R)-2-(6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole;-   2-((R)-6-(4-(2-(((R)-1,4-dioxan-2-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole;-   (R)-2-(6-(4-(2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole;-   2-((R)-6-(4-(2-(((S)-1,4-dioxan-2-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole;-   (R)-ethyl    5-(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole-2-carboxylate;-   (R)-2-(6-(4-(2-(oxetan-3-ylmethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole;-   (R)-2-(6-(4-(2-((3-fluorooxetan-3-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole;-   (R)-2-(6-(4-(2-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole;-   (R)-2-(6-(4-(2-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole;-   (R)-6-(4-(2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane;-   (R)-2-(pyrimidin-5-yl)-6-(4-(2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane;-   (R)-2-(pyrimidin-5-yl)-6-(4-(2-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane;-   (R)-6-(4-(2-(oxetan-3-ylmethoxy)phenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane;-   (R)-6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)phenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane;-   (R)-2-(pyrimidin-5-yl)-6-(4-(2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane;-   (R)-1-(2-(1-(2-(1,3,4-oxadiazol-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)-2-methylpropan-2-ol;-   2-((R)-6-(4-(2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole;-   (R)-ethyl    5-(6-(4-(2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole-2-carboxylate;-   (R)-2-(6-(4-(2-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole;-   (R)-2-(6-(4-(2-((4-methyltetrahydro-2H-pyran-4-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole;-   (R)-2-(6-(4-(2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole;-   (R)-2-(6-(4-(2-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole;-   (R)-2-(6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole;-   (R)-2-(6-(4-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole;    2-((6R)-6-(4-(5-fluoro-2-(tetrahydrofuran-3-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole;    2-((6R)-6-(4-(2-(tetrahydrofuran-3-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole;-   (R)-2-(6-(4-(2-((tetrahydro-2H-pyran-4-yl)methyl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole;-   (R)-2-(6-(4-(2-(oxazol-2-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole;-   (1S,4s)-4-(2-(1-((R)-2-(1,3,4-oxadiazol-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenyl)cyclohexan-1-ol;-   (1R,4r)-4-(2-(1-((R)-2-(1,3,4-oxadiazol-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenyl)cyclohexan-1-ol;-   (1s,4r)-4-(2-(1-((R)-2-(1,3,4-oxadiazol-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenyl)cyclohexan-1-ol;-   (1r,4r)-4-(2-(1-((R)-2-(1,3,4-oxadiazol-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenyl)cyclohexan-1-ol;-   (R)-2-(6-(4-(2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole;-   2-((R)-6-(4-(2-(((R)-1,4-dioxan-2-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole;-   2-((R)-6-(4-(2-(((S)-1,4-dioxan-2-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole;-   (R)-2-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole;-   (R)-2-(6-(4-(3-fluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole;-   (R)-2-(6-(4-(2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole;-   (R)-1-(2-(1-(2-(1,3,4-thiadiazol-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)-2-methylpropan-2-ol;-   (R)-4-(2-(1-(2-(1,3,4-thiadiazol-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)-2-methylbutan-2-ol;-   (R)-5-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)isothiazole;-   (R)-5-(6-(4-(2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,2,4-thiadiazole;-   (R)-1-(2-(1-(2-(1,2,4-thiadiazol-5-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)-2-methylpropan-2-ol;-   (R)-4-(2-(1-(2-(1,2,4-thiadiazol-5-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)-2-methylbutan-2-ol;-   (R)-5-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-3-methyl-1,2,4-thiadiazole;-   (R)-1-(5-fluoro-2-(1-(2-(4-methyloxazol-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)-2-methylpropan-2-ol;-   (R)-2-methyl-1-(2-(1-(2-(4-methyloxazol-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)propan-2-ol;-   (R)-3-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,2,4-oxadiazole;-   (R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane    formate salt;-   (R)-2-methyl-1-(2-(1-(2-(pyrimidin-5-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)propan-2-ol    formate salt;-   (R)-2-methyl-1-(2-(1-(2-(4-methylpyrimidin-5-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)propan-2-ol    formate salt;-   (R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(6-methylpyridin-3-yl)-2-azaspiro[3.4]octane    formate salt;-   (R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(2-methylpyrimidin-5-yl)-2-azaspiro[3.4]octane;-   (R)-2-(5-fluoropyridin-3-yl)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octane;-   (R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(6-methylpyrazin-2-yl)-2-azaspiro[3.4]octane;-   (R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(pyrazin-2-yl)-2-azaspiro[3.4]octane;-   (R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(3-(trifluoromethyl)pyrazin-2-yl)-2-azaspiro[3.4]octane;-   (R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(3-methylpyrazin-2-yl)-2-azaspiro[3.4]octane;-   (R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(pyridin-3-yl)-2-azaspiro[3.4]octane;-   (R)-2-(6-methylpyridin-3-yl)-6-(4-(2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane;-   (R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(4-methyl-1,3,5-triazin-2-yl)-2-azaspiro[3.4]octane;-   (R)-2-(6-chloropyridazin-3-yl)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octane;-   (R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(pyridazin-3-yl)-2-azaspiro[3.4]octane;-   (R)-6-(4-(5-chloro-2-methoxyphenyl)piperidin-1-yl)-2-(pyridazin-4-yl)-2-azaspiro[3.4]octane;-   (R)-6-(4-(2-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,5-triazin-2-yl)-2-azaspiro[3.4]octane;-   (R)-2-(3,6-dichloropyridazin-4-yl)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octane;-   (R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(pyridazin-4-yl)-2-azaspiro[3.4]octane;-   (R)-2-methyl-1-(2-(1-(2-(3-methylpyrazin-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)propan-2-ol;-   (R)-1-(2-(1-(2-(1,3,5-triazin-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)-2-methylpropan-2-ol;-   (R)-6-(4-(5-fluoro-2-methoxyphenyl)piperidin-1-yl)-2-(pyridazin-4-yl)-2-azaspiro[3.4]octane;-   (R)-6-(4-(3-fluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane;-   (R)-6-(4-(2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-2-(pyridazin-3-yl)-2-azaspiro[3.4]octane;-   (R)-6-(4-(2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-2-(5-methylpyrazin-2-yl)-2-azaspiro[3.4]octane;-   (R)-6-(4-(2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-2-(pyridazin-4-yl)-2-azaspiro[3.4]octane;-   (R)-2-(5-fluoropyridin-3-yl)-6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane;-   (R)-2-(pyrimidin-5-yl)-6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane;-   (R)-2-(6-fluoropyridin-3-yl)-6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane;-   (R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(5-methylpyrazin-2-yl)-2-azaspiro[3.4]octane;-   (R)-(6-(4-(5-fluoro-2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone;-   (R)-(6-(4-(2-(difluoromethoxy)-4-fluorophenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone;-   (R)-(6-(4-(4-fluoro-2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone;-   (R)-(6-(4-(4-fluoro-2-isopropoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone;-   (R)-(6-(4-(2-cyclopropoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone;-   (R)-(6-(4-(2-(2-fluoro-2-methylpropoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone;-   (R)-oxetan-3-yl(6-(4-(2-(thiazol-2-yloxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-3-(2-(1-(2-(oxetane-3-carbonyl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)propanenitrile;-   oxetan-3-yl((R)-6-(4-(2-(((R)-tetrahydrofuran-3-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-(6-(4-(2-isobutoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone;-   (R)-(6-(4-(2-(cyclopentyloxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone;-   (R)-(6-(4-(2-cyclobutoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone;-   (R)-(6-(4-(2-(cyclopropylmethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone;-   (R)-(6-(4-(2-ethoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone;-   (R)-(6-(4-(2-isopropoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone;-   (R)-(6-(4-(2-(2-hydroxy-2-methylpropoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone;-   (R)-(1-fluorocyclopropyl)(6-(4-(2-(pyrimidin-2-ylmethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;    (S)-(1-fluorocyclopropyl)(6-(4-(2-(pyrimidin-2-ylmethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-(1-fluorocyclopropyl)(6-(4-(2-(2-hydroxyethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (S)-(1-fluorocyclopropyl)(6-(4-(2-(2-hydroxyethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-(6-(4-(2-(cyclopropylmethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (R)-(6-(4-(2-(cyclopropylmethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (R)-1-(2-(2-(1-(2-(1-fluorocyclopropane-1-carbonyl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)ethyl)pyrrolidin-2-one    formate salt;-   (S)-1-(2-(2-(1-(2-(1-fluorocyclopropane-1-carbonyl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)ethyl)pyrrolidin-2-one    formate salt;-   (R)-(1-fluorocyclopropyl)(6-(4-(2-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (S)-(1-fluorocyclopropyl)(6-(4-(2-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-(1-fluorocyclopropyl)(6-(4-(2-((5-methyl-1,3,4-thiadiazol-2-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (S)-(1-fluorocyclopropyl)(6-(4-(2-((5-methyl-1,3,4-thiadiazol-2-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-(6-(4-(2-ethoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (S)-(6-(4-(2-ethoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (R)-(6-(4-(2-(cyclopropylmethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (R)-(6-(4-(2-(cyclopropylmethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (R)-(6-(4-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (S)-(6-(4-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (R)-(1-fluorocyclopropyl)(6-(4-(2-((2-methyloxazol-5-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (S)-(1-fluorocyclopropyl)(6-(4-(2-((2-methyloxazol-5-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-(1-fluorocyclopropyl)(6-(4-(2-((5-methyl-1,3,4-oxadiazol-2-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (S)-(1-fluorocyclopropyl)(6-(4-(2-((5-methyl-1,3,4-oxadiazol-2-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-(1-fluorocyclopropyl)(6-(4-(2-((5-methyl-1,2,4-oxadiazol-3-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (S)-(1-fluorocyclopropyl)(6-(4-(2-((5-methyl-1,2,4-oxadiazol-3-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-(1-fluorocyclopropyl)(6-(4-(2-((5-methyl-1,3,4-oxadiazol-2-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (S)-(1-fluorocyclopropyl)(6-(4-(2-((5-methyl-1,3,4-oxadiazol-2-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-(1-fluorocyclopropyl)(6-(4-(2-((5-methyl-1,2,4-oxadiazol-3-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (S)-(1-fluorocyclopropyl)(6-(4-(2-((5-methyl-1,2,4-oxadiazol-3-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-(1-fluorocyclopropyl)(6-(4-(2-(3,3,3-trifluoropropoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (S)-(1-fluorocyclopropyl)(6-(4-(2-(3,3,3-trifluoropropoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-(1-fluorocyclopropyl)(6-(4-(2-(3-hydroxy-3-methylbutoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (S)-(1-fluorocyclopropyl)(6-(4-(2-(3-hydroxy-3-methylbutoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-(6-(4-(2-(3-hydroxy-3-methylbutoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone;-   (R)-oxetan-3-yl(6-(4-(2-(2-(trifluoromethoxy)ethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-oxetan-3-yl(6-(4-(2-(2-(oxetan-3-yloxy)ethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-(1-fluorocyclopropyl)(6-(4-(2-(3-methoxy-3-methylbutoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (S)-(1-fluorocyclopropyl)(6-(4-(2-(3-methoxy-3-methylbutoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-oxetan-3-yl(6-(4-(2-(3,3,3-trifluoropropoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-(6-(4-(2-(2-methoxy-2-methylpropoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone;-   (R)-oxetan-3-yl(6-(4-(2-((1-(trifluoromethyl)cyclopropyl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-(6-(4-(2-(2,2-difluoroethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone;-   (R)-oxetan-3-yl(6-(4-(2-(2-(oxetan-3-yl)ethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (S)-(6-(4-(5-chloro-2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (R)-(6-(4-(5-chloro-2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (S)-(6-(4-(5-chloro-2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (R)-(6-(4-(5-chloro-2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (S)-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone;-   (R)-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone;-   (S)-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone;-   (R)-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone;-   (S)-(6-(4-(2-(difluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone;-   (R)-(6-(4-(2-(difluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone    citrate salt;-   (S)-(6-(4-(2-(difluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone;-   (R)-(6-(4-(2-(difluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone    citrate salt;-   (S)-oxetan-3-yl(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-oxetan-3-yl(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-(1-fluorocyclopropyl)(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (S)-(1-fluorocyclopropyl)(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-(1-fluorocyclopropyl)(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (S)-(1-fluorocyclopropyl)(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-(6-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (S)-(6-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (R)-(6-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (S)-(6-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (R)-(1-fluorocyclopropyl)(6-(4-(2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (S)-(1-fluorocyclopropyl)(6-(4-(2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-(1-fluorocyclopropyl)(6-(4-(2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (S)-(1-fluorocyclopropyl)(6-(4-(2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-(1-fluorocyclopropyl)(6-(4-(2-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (S)-(1-fluorocyclopropyl)(6-(4-(2-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-(1-fluorocyclopropyl)(6-(4-(2-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (S)-(1-fluorocyclopropyl)(6-(4-(2-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-(6-(4-(5-fluoro-2-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (S)-(6-(4-(5-fluoro-2-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (R)-(6-(4-(5-fluoro-2-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (S)-(6-(4-(5-fluoro-2-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (R)-(6-(4-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (S)-(6-(4-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (R)-(6-(4-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (S)-(6-(4-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (R)-(1-fluorocyclopropyl)(6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (S)-(1-fluorocyclopropyl)(6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-6-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-(5-fluoropyridin-3-yl)-2-azaspiro[3.4]octane;-   (S)-6-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-(5-fluoropyridin-3-yl)-2-azaspiro[3.4]octane;-   (R)-6-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-(5-fluoropyridin-3-yl)-2-azaspiro[3.4]octane;-   (S)-6-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-(5-fluoropyridin-3-yl)-2-azaspiro[3.4]octane;-   (R)-6-(4-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane;-   (S)-6-(4-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane;-   (R)-6-(4-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane;-   (S)-6-(4-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane;-   (R)-6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane;-   (S)-6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane;-   (R)-6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane;-   (S)-6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane;-   (R)-6-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane;-   (S)-6-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane;-   (R)-6-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane;-   (S)-6-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane;-   (S)-2-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)oxazole;-   (R)-2-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)oxazole;-   (S)-2-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)oxazole;-   (R)-2-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)oxazole;-   (R)-2-(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)oxazole;-   (S)-2-(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)oxazole;-   (R)-2-(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)oxazole;-   (S)-2-(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)oxazole;-   (R)-2-(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole;-   (S)-2-(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole;-   (R)-2-(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole;-   (S)-2-(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole;-   (R)-2-(6-(4-(2-(difluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole;-   (S)-2-(6-(4-(2-(difluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole;-   (R)-2-(6-(4-(2-(difluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole;-   (S)-2-(6-(4-(2-(difluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole;-   (R)-5-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,2,4-thiadiazole;-   (S)-5-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,2,4-thiadiazole;-   (R)-5-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,2,4-thiadiazole;-   (S)-5-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,2,4-thiadiazole;-   (R)-(6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (S)-(6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (R)-(6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (S)-(6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (R)-(6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (S)-(6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (R)-(6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;    and-   (S)-(6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone,    or a pharmaceutically acceptable salt thereof.

In one embodiment, provided herein is a compound selected from the groupconsisting of:

-   (R)-2-(6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole;-   (S)-2-(6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole;-   (R)-(1-fluorocyclopropyl)(6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (S)-(1-fluorocyclopropyl)(6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-2-(pyrimidin-5-yl)-6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane;-   (S)-oxetan-3-yl(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;    and-   (R)-oxetan-3-yl(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone,    or a pharmaceutically acceptable salt thereof.

In one embodiment, provided herein is a compound selected from the groupconsisting of:

-   (R)-2-(6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole,    having the following structure:

(R)-(1-fluorocyclopropyl)(6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone,having the following structure:

(R)-2-(pyrimidin-5-yl)-6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane,having the following structure:

and(R)-oxetan-3-yl(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone,having the following structure:

or a pharmaceutically acceptable salt thereof.

In one embodiment, provided herein is a pharmaceutical compositioncomprising a compound provided herein or a pharmaceutically acceptablesalt thereof.

In one embodiment, provided herein is a method for the treatment of a M4related a condition, disease or disorder comprising administration of atherapeutically effective amount of a compound provided herein or apharmaceutically acceptable salt thereof to a patient in need oftreatment thereof.

In one embodiment, provided herein is a method for the treatment ofpsychosis comprising administration of a therapeutically effectiveamount of a compound provided herein or a pharmaceutically acceptablesalt thereof to a patient in need of treatment thereof. In someembodiments, the psychosis is associated with schizophrenia,schizoaffective disorder, psychotic depression, bipolar disorder withpsychotic features, Alzheimer's disease, Parkinson's Disease,post-traumatic stress disorder or frontotemporal dementia. In preferredembodiments, the psychosis is associated with Alzheimer's disease.

In one embodiment, provided herein is a method for the treatment ofcognitive dysfunction comprising administration of a therapeuticallyeffective amount of a compound provided herein or a pharmaceuticallyacceptable salt thereof to a subject in need of treatment thereof.

In one embodiment, provided herein is a method for the treatment of ahyperkinetic movement disorder comprising administration of atherapeutically effective amount of a compound provided herein or apharmaceutically acceptable salt thereof to a subject in need oftreatment thereof.

In one embodiment, provided herein is a method for treatment ofsubstance use disorders comprising administration of a therapeuticallyeffective amount of a compound provided herein or a pharmaceuticallyacceptable salt thereof to a subject in need of treatment thereof.

In one embodiment, provided herein is a method of treating a condition,disease or disorder which is treated with a M4 receptor agonistcomprising administration of a therapeutically effective amount of acompound provided herein or a pharmaceutically acceptable salt thereofand an antidepressant to a subject in need of treatment thereof.

In one embodiment, provided herein is a method for the treatment of acondition, disease or disorder which is treated with a M4 receptoragonist comprising administration of a therapeutically effective amountof a compound provided herein or a pharmaceutically acceptable saltthereof in conjunction with computer-assisted psychosocial or behavioraltherapy.

5. BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the effect of Example 2H, Example 6E, Example 8C, andExample 9B on the hyperactivity in mice induced by the stimulantd-amphetamine using a mouse amphetamine induced hyperlocomotion assay.

FIG. 2 illustrates the effect of Example 12A on the hyperactivity inmice induced by the stimulant d-amphetamine using a mouse amphetamineinduced hyperlocomotion assay.

6. DETAILED DESCRIPTION 6.1. Definitions

“Alkyl” as used herein refers to a monovalent saturated hydrocarbonchain having the specified number of carbon atoms. For example, C₁₋₃alkyl refers to an alkyl group having from 1 to 3 carbon atoms. Alkylgroups may be optionally substituted with one or more substituents asdefined in Formula (I). Alkyl groups may be straight or branched.Representative branched alkyl groups have one, two, or three branches.Examples of alkyl groups include, but are not limited to, methyl, ethyl,propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, sec-butyl,and t-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl.

“Cycloalkyl” as used herein refers to a saturated hydrocarbon ringsystem having the specified number of carbon atoms. Cycloalkyl groupsare monocyclic or bicyclic ring systems. For example, C₃₋₇ cycloalkylrefers to a cycloalkyl group having from 3 to 7 carbon atoms. Cycloalkylgroups may be optionally substituted with one or more substituents asdefined in Formula (I). Examples of cycloalkyl groups include, but arenot limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

“Halo” or “halogen” as used herein refers to a fluoro, chloro, or bromogroup.

“Haloalkyl” as used herein refers to an alkyl group, having thespecified number of carbon atoms, wherein at least one hydrogen atomattached to a carbon atom within the alkyl group is replaced with halo.The number of halo substituents includes, but is not limited to, 1, 2,3, 4, 5, or 6 substituents. Haloalkyl includes, but is not limited to,monofluoromethyl, difluoroethyl, and trifluoromethyl.

“Heteroaryl” as used herein refers to an aromatic ring system containingone or more heteroatoms. Heteroaryl groups containing more than oneheteroatom may contain different heteroatoms. Heteroaryl groups may beoptionally substituted with one or more substituents as defined inFormula (I). Heteroaryl groups may be monocyclic ring systems or fusedbicyclic ring systems. Monocyclic heteroaryl rings have from 5 to 6 ringatoms. Bicyclic heteroaryl rings have from 8 to 10 member atoms.Bicyclic heteroaryl rings include those ring systems wherein aheteroaryl ring is fused to a phenyl ring. Heteroaryl includes, but isnot limited to, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl,oxadiazolyl (including 1,3,4-oxadiazolyl and 1,2,4-oxadiazolyl),thiazolyl, isothiazolyl, thiadiazolyl (including 1,3,4-thiadiazolyl),furanyl, furanzanyl, thienyl, triazolyl, pyridinyl (including 2-, 3-,and 4-pyridinyl), pyrimidinyl, pyridazinyl, pyrazinyl, trazinyl,tetrazinyl, tetrazolyl, indonyl, isoindolyl, indolizinyl, indazolyl,purinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl,benzimidazolyl, benzopyranyl, benzopyranyl, benzoxazolyl,benzoisoxazolyl, benzofuranyl, benzothiazolyl, benzothienyl,naphthyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, tetrazolo[1,5-a]pyridinyl,imidazo[2,1-b][1,3,4]thiadiazolyl and the like.

“5-6 membered heteroaryl” as used herein refers to a heteroaryl groupdefined above, having 5 or 6 ring atoms and containing 1 to 4heteroatoms. Examples of a 5-6 membered heteroaryl include, but are notlimited to, thiazole, oxazole, isoxazole, 1,3,4-thiadiazole,1,2,4-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,5-thiadiazole,1H-imidazole, 1H-pyrazole, pyridine, pyrimidine, 1,3,5-triazine and thelike.

“Heteroatom” as used herein refers to a nitrogen, oxygen, or sulfuratom.

“Heterocyclic” or “heterocycloalkyl” as used herein refers to asaturated or unsaturated monocyclic or bicyclic ring containing from 1to 4 heteroatoms. Heterocyclic ring systems are not aromatic.Heterocyclic groups containing more than one heteroatom may containdifferent heteroatoms. Heterocyclic includes ring systems wherein asulfur atom is oxidized to form SO or SO₂. Heterocyclic groups may beoptionally substituted with one or more substituents as defined inFormula (I). Heterocyclic groups are monocyclic, bicyclic, spiro, orfused or bridged bicyclic ring systems. Monocyclic heterocyclic ringshave 3 to 7 ring atoms. Examples of monocyclic heterocyclic groupsinclude pyranyl, tetrahydropyranyl, oxetanyl, tetrahydrofuranyl,dihydrofuranyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, piperazinyl,piperidinyl, 1,3-dioxolanyl, imidazolidinyl, imidazolinyl, pyrrolinyl,pyrrolidinyl, tetrahydropyranyl, dihydropyranyl, oxathiolanyl,dithiolanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dithianyl, oxathianyl,thiomorpholinyl, tetrahydro-thiopyran 1,1-dioxide, 1,4-diazepanyl, andthe like. Examples of bicyclic heterocyclic groups include3-oxabicyclo[3.1.0]hexane and the like. Examples of bridged heterocyclicgroups include 2-azabicyclo[2.2.1]heptanyl and the like. Examples ofspiro heterocyclic groups include 2-oxaspiro[3.3]heptanyl and the like.

“4 to 6 membered heterocyclic” or “4 to 6 membered heterocycloaryl” asused herein refers to a heterocyclic group as defined above, having from4 to 6 ring atoms and containing from 1 to 3 heteroatoms. Examples of 4to 6 membered heterocyclic include but are not limited to, oxetanyl,pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, 1,4-diazepanyl,3-oxabicyclo[3.1.0]hexanyl and the like.

“5 to 6 membered heterocyclic” or “5 to 6 membered heterocycloaryl” asused herein refers to a heterocyclic group as defined above, having from5 to 6 ring atoms and containing from 1 to 3 heteroatoms. Examples of 5to 6 membered heterocyclic include but are not limited to, pyrrolidinyl,morpholinyl, piperazinyl, piperidinyl, 1,4-diazepanyl,3-oxabicyclo[3.1.0]hexanyl and the like.

“3 to 9 membered heterocyclic” or “3 to 9 membered heterocycloaryl” asused herein refers to a heterocyclic group as defined above, having from3 to 9 ring atoms and containing from 1 to 3 heteroatoms. Examples of3-9 membered heterocyclic include but are not limited to, pyrrolidinyl,morpholinyl, piperazinyl, piperidinyl, 1,4-diazepanyl,2-oxaspiro[3.3]heptanyl, 3-oxabicyclo[3.1.0]hexanyl and the like.

“Optionally substituted” as used herein indicates that a group, such asan alkyl, heteroaryl and heterocyclic, may be unsubstituted or the groupmay be substituted with one or more substituents as defined in Formula(I).

“Salt” or “salts” as used herein refers to an acid addition or baseaddition salt of a compound provided herein. “Salts” include inparticular “pharmaceutically acceptable salts”. “Pharmaceuticallyacceptable salts” as used herein refers to salts that retain thebiological effectiveness and properties of the compounds according toFormula (I) and, which typically are not biologically or otherwiseundesirable. In many cases, the compounds according to Formula (I) arecapable of forming acid and/or base salts by virtue of the presence ofamino and/or carboxyl groups or groups similar thereto. The skilledartisan will appreciate that salts, including pharmaceuticallyacceptable salts, of the compounds according to Formula (I) may beprepared. These salts may be prepared in situ during the final isolationand purification of the compound, or by separately reacting the purifiedcompound in its free acid or free base form with a suitable base oracid, respectively.

Pharmaceutically acceptable acid addition salts can be formed withinorganic acids and organic acids. Inorganic acids from which salts canbe derived include, for example, hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acidsfrom which salts can be derived include, for example, acetic acid,propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid,succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid,mandelic acid, methanesulfonic acid, ethanesulfonic acid,toluenesulfonic acid, sulfosalicylic acid, and the like.

Pharmaceutically acceptable base addition salts can be formed withinorganic and organic bases, such as carboxylate, sulfonate andphosphate salts.

In certain embodiments, provided herein are compounds according toFormula (I) in acetate, ascorbate, adipate, aspartate, benzoate,besylate, bromide/hydrobromide, bicarbonate/carbonate,bisulfate/sulfate, camphorsulfonate, caprate, chloride/hydrochloride,chlortheophyllonate, citrate, ethandisulfonate, formate, fumarate,gluceptate, gluconate, glucuronate, glutamate, glutarate, glycolate,hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate,laurylsulfate, malate, maleate, malonate, mandelate, mesylate,methylsulphate, mucate, naphthoate, napsylate, nicotinate, nitrate,octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogenphosphate/dihydrogen phosphate, polygalacturonate, propionate, sebacate,stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate,trifenatate, trifluoroacetate or xinafoate salt form. In certainembodiments, provided herein are compounds according to Formula (I) informate or citrate salt form.

“Isomers” refers to different compounds according to Formula (I) thathave the same molecular formula but differ in arrangement andconfiguration of the atoms.

“Optical isomer” or “stereoisomer” refers to any of the various stereoisomeric configurations which may exist for a given compound providedherein and includes geometric isomers. It is understood that asubstituent may be attached at a chiral center of a carbon atom.Therefore, compounds provided herein include enantiomers, diastereomersor racemates of the compound.

Depending on the choice of the starting materials and procedures, thecompounds according to Formula (I) can be present in the form of one ofthe possible stereoisomers or as mixtures thereof, for example as pureoptical isomers, or as stereoisomer mixtures, such as racemates anddiastereoisomer mixtures, depending on the number of asymmetric carbonatoms. The compounds according to Formula (I) provided herein are meantto include all such possible stereoisomers, including racemic mixtures,diastereomeric mixtures and optically pure forms. Optically active (R)-and (S)-stereoisomers may be prepared using chiral synthons or chiralreagents, or resolved using conventional techniques. If the compoundcontains a double bond, the substituent may be E or Z configuration. Ifthe compound contains a disubstituted cycloalkyl, the cycloalkylsubstituent may have a cis- or trans-configuration. All tautomeric formsare also intended to be included.

Any asymmetric atom (e.g., carbon or the like) of the compoundsaccording to Formula (I) can be present in racemic or enantiomericallyenriched, for example the (R)-, (S)- or (R,S)-configuration. In certainembodiments, each asymmetric atom has at least 50% enantiomeric excess,at least 60% enantiomeric excess, at least 70% enantiomeric excess, atleast 80% enantiomeric excess, at least 90% enantiomeric excess, atleast 95% enantiomeric excess, or at least 99% enantiomeric excess inthe (R)- or (S)-configuration. Substituents at atoms with unsaturateddouble bonds may, if possible, be present in cis-(Z)— or trans-(E)-form.

Accordingly, a compound provided herein can be in the form of one of thepossible stereoisomers, rotamers, atropisomers, tautomers or mixturesthereof, for example, as substantially pure geometric (cis or trans)stereoisomers, diastereomers, optical isomers (antipodes), racemates ormixtures thereof.

Any resulting mixtures of stereoisomers can be separated on the basis ofthe physicochemical differences of the constituents, into the pure orsubstantially pure geometric or optical isomers, diastereomers,racemates, for example, by chromatography and/or fractionalcrystallization.

Any resulting racemates of the compounds according to Formula (I) or ofintermediates thereof can be resolved into the optical antipodes byknown methods, e.g., by separation of the diastereomeric salts thereof,obtained with an optically active acid or base, and liberating theoptically active acidic or basic compound. In particular, a basic moietymay thus be employed to resolve the compounds according to Formula (I)into their optical antipodes, e.g., by fractional crystallization of asalt formed with an optically active acid, e.g., tartaric acid,dibenzoyl tartaric acid, diacetyl tartaric acid, di-O,O′-p-toluoyltartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid.Racemic compounds according to Formula (I) or racemic intermediates canalso be resolved by chiral chromatography, e.g., high pressure liquidchromatography (HPLC) using a chiral adsorbent.

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulae given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Isotopes that can be incorporated intocompounds according to Formula (I) include, for example, isotopes ofhydrogen.

Further, incorporation of certain isotopes, particularly deuterium(i.e., ²H or D) may afford certain therapeutic advantages resulting fromgreater metabolic stability, for example increased in vivo half-life orreduced dosage requirements or an improvement in therapeutic index ortolerability. It is understood that deuterium in this context isregarded as a substituent of a compound provided herein. Theconcentration of deuterium, may be defined by the isotopic enrichmentfactor. “Isotopic enrichment factor” as used herein means the ratiobetween the isotopic abundance and the natural abundance of a specifiedisotope. If a substituent in a compound provided herein is denoted asbeing deuterium, such compound has an isotopic enrichment factor foreach designated deuterium atom of at least 3500 (52.5% deuteriumincorporation at each designated deuterium atom), at least 4000 (60%deuterium incorporation), at least 4500 (67.5% deuterium incorporation),at least 5000 (75% deuterium incorporation), at least 5500 (82.5%deuterium incorporation), at least 6000 (90% deuterium incorporation),at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97%deuterium incorporation), at least 6600 (99% deuterium incorporation),or at least 6633.3 (99.5% deuterium incorporation). It should beunderstood that the term “isotopic enrichment factor” can be applied toany isotope in the same manner as described for deuterium.

For example, Formula (I) may be deuterated as shown in Formula (Ic):

or a pharmaceutically acceptable salt thereof, wherein R³ and R⁷ are asdefined in Formula (I); and R^(D1), R^(D2), R^(D5), and R^(D8)—R^(D27)are each independently D or halogen.

Other examples of isotopes that can be incorporated into compoundsaccording to Formula (I) include isotopes of hydrogen, carbon, nitrogen,oxygen, phosphorous, fluorine, and chlorine, such as ³H, ¹¹C, ¹³C, ¹⁴C,¹⁵N, ¹⁸F ³¹P, ³²P, ³⁵S, ³⁶Cl, ¹²³I, ¹²⁴I, ¹²⁵I respectively. Accordinglyit should be understood that compounds according to Formula (I) includescompounds that incorporate one or more of any of the aforementionedisotopes, including for example, radioactive isotopes, such as ³H and¹⁴C, or those into which non-radioactive isotopes, such as ²H and ¹³Care present. Such isotopically labelled compounds are useful inmetabolic studies (with ¹⁴C), reaction kinetic studies (with, forexample ²H or ³H), detection or imaging techniques, such as positronemission tomography (PET) or single-photon emission computed tomography(SPECT) including drug or substrate tissue distribution assays, or inradioactive treatment of patients. In particular, an ¹⁸F or labeledcompound may be particularly desirable for PET or SPECT studies.Isotopically-labeled compounds according to Formula (I) can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described in the accompanying Examplesand preparations using an appropriate isotopically-labeled reagents inplace of the non-labeled reagent previously employed.

“Administration” and “administering” and “administer” as used hereinrefer to the manner in which a compound provided herein (e.g., acompound according to Formula (I)) is presented to a subject.

“Subject” or “patient” as used herein refers to a living organismsuffering from one or more of the diseases or disorders described herethat can be treated by administration of a pharmaceutical compositiondescribed herein. Examples of subjects include mammals (e.g., humans andanimals such as dogs, cows, horses, monkeys, pigs, guinea pigs, sheep,goats, cats, mice, rabbits, rats, and transgenic non-human animals). Incertain embodiments, the subject is a primate. In certain embodiments,the subject is a human, e.g., a human suffering from, at risk ofsuffering from, or potentially capable of suffering from a diseasedescribed herein. In particular embodiments, the subject is an adulthuman at least about 18 years of age. In particular embodiments, thesubject is an adult human from about 18 to about 75 years of age. Insome embodiments, the subject is a human child up to about 18 years ofage.

“Treat”, “treating” or “treatment” of any disease or disorder as usedherein refers to relieve, alleviate, delay, reduce, reverse, or improveat least one symptom of a condition in a subject. The term “treating”may also mean to arrest, delay the onset (i.e., the period prior toclinical manifestation of a disease) and/or reduce the risk ofdeveloping or worsening a condition. In certain embodiments, the term“treating” refers to relieving, alleviating, delaying of progression,reducing, reversing, or improving at least one symptom of a conditionselected from psychosis, including psychosis associated withschizophrenia, schizoaffective disorder, psychotic depression, bipolardisorder with psychotic features, Alzheimer's Disease, Parkinson'sDisease, post-traumatic stress disorder, and frontotemporal dementia,hyperkinetic movement disorders, including but not limited to Tourette'sSyndrome, chorea and tardive dyskinesia, cognitive dysfunction,including but not limited to cognitive dysfunction associated withschizophrenia, Alzheimer's Disease, frontotemporal dementia,schizoaffective disorder, and depression; and/or substance usedisorders.

“Prevent”, “preventing” or “prevention” of any disease or disorder asused herein refers to the prophylactic treatment of the disease ordisorder; or delaying the onset or progression of the disease ordisorder.

“Pharmaceutical composition” as used herein refers to a compoundprovided herein, or a pharmaceutically acceptable salt thereof, togetherwith at least one pharmaceutically acceptable carrier, in a formsuitable for oral or parenteral administration.

“Pharmaceutically acceptable carrier” as used herein refers to asubstance useful in the preparation or use of a pharmaceuticalcomposition and includes, for example, suitable diluents, solvents,dispersion media, surfactants, antioxidants, preservatives, isotonicagents, buffering agents, emulsifiers, absorption delaying agents,salts, drug stabilizers, binders, excipients, disintegration agents,lubricants, wetting agents, sweetening agents, flavoring agents, dyes,and combinations thereof, as would be known to those skilled in the art(see, for example, Remington The Science and Practice of Pharmacy,22^(nd) Ed. Pharmaceutical Press, 2013, pp. 1049-1070).

A “therapeutically effective amount” of a compound provided herein asused herein refers to an amount of the compound that will elicit thebiological or medical response of a subject, for example, increaseenzyme or a protein activity, or ameliorate symptoms, alleviateconditions, slow or delay disease progression, or prevent a disease,etc. In one embodiment, the term “a therapeutically effective amount”refers to the amount of the compound provided herein that, whenadministered to a subject, is effective to (1) at least partiallyalleviate, prevent and/or ameliorate a condition, or a disorder or adisease (i) mediated by M4, or (ii) associated with M4 activity, or(iii) characterized by activity (normal or abnormal) of M4; or (2)increase the activity of M4. In another embodiment, the term “atherapeutically effective amount” refers to the amount of the compoundprovided herein that, when administered to a cell, or a tissue, or anon-cellular biological material, or a medium, is effective to increasethe activity of M4.

“Inhibit”, “inhibition” or “inhibiting” as used herein refers to thereduction or suppression of a given condition, symptom, or disorder, ordisease, or a significant decrease in the baseline activity of abiological activity or process.

A subject is “in need of” a treatment if such subject would benefitbiologically, medically or in quality of life from such treatment.

“Substance use disorder” or “SUD” as used herein is defined withreference to DSM-5 criteria (i.e., according to the Diagnostic andStatistical Manual of Mental Disorders. 5^(th) Edition, Washington,D.C.: American Psychiatric Association, 2013; hereinafter “DSM-5”), theentire contents of which are incorporated herein by reference. The term“substance use disorder” as used herein is defined as when the recurrentuse of alcohol and/or drugs causes clinically and functionallysignificant impairment, such as health problems, disability, and failureto meet major responsibilities at work, school, or home. According tothe DSM-5, a diagnosis of substance use disorder is based on evidence ofimpaired control, social impairment, risky use, and pharmacologicalcriteria. Substance use disorder includes, for example, alcohol usedisorder, tobacco use disorder, cannabis use disorder, stimulant usedisorder, hallucinogen use disorder and opioid use disorder.

“Psychosocial or behavioral therapy” as used herein refers to, but notlimited to, cognitive behavioral therapy (e.g., as described in Arch.Gen. Psychiatry 1999; 56:493-502), interpersonal therapy (e.g., asdescribed in Psychol Addict Behav 2009; 23(1): 168-174), contingencymanagement based therapy e.g., as described in Psychol Addict Behav2009; 23(1): 168-174; in J. Consul. Clin. Psychol. 2005; 73(2): 354-59;or in Case Reports in Psychiatry, Vol. 2012, Article ID 731638),community reinforcement approach based therapy (e.g., as described inDrug Alcohol Depend 2004; 74:1-13), motivational interviewing basedtherapy (e.g., as described in J. Consul. Clin. Psychol. 2001; 69(5):858-62), motivational enhancement based therapy (e.g., as described inDrug Alcohol Depend 2007, 91:97-101) or meditation based therapy, suchas transcendental meditation based therapy (e.g., as described inAddiction 2004; 99(7):862-874 or J. Consul. Clin. Psychol. 2000; 68(3):515-52); in particular contingency management based therapy.

“Standardized psychological treatment” or “standardized psychologicalsupport” as used herein refers to standard counselling sessions, forexample once a week, in particular counselling focused on cocaineconsumption.

“Computer-assisted” or “computer-assistance” as used herein refers topsychosocial or behavioral therapy comprising the use of electronic ordigital tools such as online tools, smartphones, laptops, tablets,wireless devices or health Apps.

Unless specified otherwise, “a compound provided herein” or “compoundsprovided herein” refers to compounds of Formula (I) and subformulaethereof, including Formula (Ia), (Ib), and (Ic), and any exemplifiedcompounds and salts thereof, as well as all stereoisomers (includingdiastereoisomers and enantiomers), rotamers, tautomers and isotopicallylabeled compounds (including deuterium substitutions), as well asinherently formed moieties.

“A,” “an,” “the” and similar terms as used herein (especially in thecontext of the claims) are to be construed to cover both the singularand plural unless otherwise indicated herein or clearly contradicted bythe context.

Throughout this specification and in the claims that follow, unless thecontext requires otherwise, the word “comprise”, or variations such as“comprises” or “comprising”, should be understood to imply the inclusionof a stated integer or step or group of integers or steps but not theexclusion of any other integer or step or group of integers or steps.

If there is a discrepancy between a depicted structure and a chemicalname given to that structure, the depicted structure is to be accordedmore weight. In addition, if the stereochemistry of a structure or aportion of a structure is not indicated with, for example, bold ordashed lines, the structure or portion of the structure is to beinterpreted as encompassing all stereoisomers of the structure ofportion of the structure.

All methods described herein can be performed in any suitable orderunless otherwise indicated herein or otherwise clearly contradicted bycontext. The use of any and all examples, or exemplary language (e.g.,“such as”) provided herein is intended merely to better illuminate theinvention and does not pose a limitation on the scope of the inventionotherwise claimed.

6.2. Compounds

In one embodiment, provided herein is a compound according to Formula(I)

or a pharmaceutically acceptable salt thereof, wherein

R¹ is halogen or hydrogen;

R² is halogen or hydrogen;

R³ is

-   -   C₁₋₆ alkyl, said alkyl is optionally substituted with one or two        substituents independently selected from the group consisting of        4 to 6-membered heterocycloalkyl and —OH,    -   5 to 6-membered heteroaryl,    -   3 to 6-membered cycloalkyl, said cycloalkyl is optionally        substituted with one —OH,    -   5 to 6-membered heterocycloalkyl, said heterocycloalkyl is        optionally substituted with one —OH, or    -   —OR⁴;

R⁴ is

-   -   —CF₃,    -   —CF₂H,    -   C₁₋₆ alkyl, said alkyl is optionally substituted with one or two        R⁶,    -   3 to 6-membered cycloalkyl,    -   4 to 7-membered heterocycloalkyl, said heterocycloalkyl is        optionally substituted with one R⁶,    -   5 to 6-membered heteroaryl, or    -   R⁴ is one of the following groups:

R⁵ is halogen or hydrogen;

each R⁶ is independently

-   -   halogen,    -   —OH,    -   —CF₃,    -   —CF₂H,    -   cyano,    -   —OCF₃,    -   —OCH₃,    -   —O-heterocycloalkyl,    -   C₁-C₄ alkyl,    -   4 to 7-membered heterocycloalkyl, said heterocycloalkyl is        optionally substituted with one or two substituents        independently selected from the group consisting of halogen,        —OH, and C₁₋₃ alkyl,    -   5 to 6-membered heteroaryl, said heteroaryl is optionally        substituted with one or two C₁₋₃ alkyl,    -   3 to 6-membered cycloalkyl, said cycloalkyl is optionally        substituted with one —CF₃, or    -   each of R⁶ is independently one of the following groups:

R⁷ is

-   -   a 5 to 6-membered heteroaryl, said heteroaryl is optionally        substituted with one substituent selected from the group        consisting of C₁-C₆ alkyl, —CF₃, and halogen, or    -   C(O)R⁸; and

R⁸ is

-   -   3 to 6-membered cycloalkyl, said cycloalkyl is optionally        substituted with one halogen, or    -   4 to 6-membered heterocycloalkyl.

In one embodiment, provided herein is a compound according to Formula(Ia)

or a pharmaceutically acceptable salt or stereoisomer thereof.

In one embodiment, provided herein is a compound according to Formula(Ib)

or a pharmaceutically acceptable salt or stereoisomer thereof.

In one embodiment, R¹ is selected from the group consisting of H,chloro, and fluoro.

In one embodiment, R² is H or fluoro.

In one embodiment, R⁵ is H or fluoro.

In one embodiment, R¹, R², and R⁵ are H.

In one embodiment, R³ is selected from the group consisting of:

In another embodiment, R³ is —OR⁴.

In one embodiment, R⁴ is selected from the group consisting of —CH₃,—CF₃, —CF₂H, —CH₂CH₃, —CH(CH₃)₂, —CH₂CF₂H, —CH₂CH₂F, —(CH₂)₂CF₃,—CH₂C(CH₃)₂F, —(CH₂)₂OCF₃, —(CH₂)₂OH, —(CH₂)₂OCH₃, —CH₂C(CH₃)₂OH,—(CH₂)₂C(CH₃)₂OH, —(CH₂)₂C(CH₃)₂OCH₃, —CH₂C(CH₃)₂OCH₃, —(CH₂)₂CN, and—CH₂CH(CH₃)₂. In another embodiment, R⁴ is selected from the groupconsisting of:

In one embodiment, R⁷ is 5 to 6-membered heteroaryl or —C(O)R. Inanother embodiment. R⁷ is

In other embodiments, R⁷ is —C(O)R⁸.

In one embodiment, R⁸ is 4 to 6-membered heterocycloalkyl or 3 to6-membered cycloalkyl. In another embodiment, R⁸ is 4 to 6-memberedheterocycloalkyl. In other preferred embodiments, R⁸ is

In certain embodiments, R⁸ is 3 to 6-membered cycloalkyl, said 3 to6-membered cycloalkyl is substituted with one halogen.

In one embodiment, provided herein is a compound selected from the groupconsisting of:

-   (R)-2-(6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole;-   (R)-2-(6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole;-   2-((R)-6-(4-(2-(((R)-1,4-dioxan-2-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole;-   (R)-2-(6-(4-(2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole;-   2-((R)-6-(4-(2-(((S)-1,4-dioxan-2-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole;-   (R)-ethyl    5-(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole-2-carboxylate;-   (R)-2-(6-(4-(2-(oxetan-3-ylmethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole;-   (R)-2-(6-(4-(2-((3-fluorooxetan-3-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole;-   (R)-2-(6-(4-(2-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole;-   (R)-2-(6-(4-(2-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole;-   (R)-6-(4-(2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane;-   (R)-2-(pyrimidin-5-yl)-6-(4-(2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane;-   (R)-2-(pyrimidin-5-yl)-6-(4-(2-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane;-   (R)-6-(4-(2-(oxetan-3-ylmethoxy)phenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane;-   (R)-6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)phenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane;-   (R)-2-(pyrimidin-5-yl)-6-(4-(2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane;-   (R)-1-(2-(1-(2-(1,3,4-oxadiazol-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)-2-methylpropan-2-ol;-   2-((R)-6-(4-(2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole;-   (R)-ethyl    5-(6-(4-(2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole-2-carboxylate;-   (R)-2-(6-(4-(2-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole;-   (R)-2-(6-(4-(2-((4-methyltetrahydro-2H-pyran-4-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole;-   (R)-2-(6-(4-(2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole;-   (R)-2-(6-(4-(2-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole;-   (R)-2-(6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole;-   (R)-2-(6-(4-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole;    2-((6R)-6-(4-(5-fluoro-2-(tetrahydrofuran-3-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole;    2-((6R)-6-(4-(2-(tetrahydrofuran-3-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole;-   (R)-2-(6-(4-(2-((tetrahydro-2H-pyran-4-yl)methyl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole;-   (R)-2-(6-(4-(2-(oxazol-2-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole;    (1S,4s)-4-(2-(1-((R)-2-(1,3,4-oxadiazol-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenyl)cyclohexan-1-ol;-   (1R,4r)-4-(2-(1-((R)-2-(1,3,4-oxadiazol-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenyl)cyclohexan-1-ol;-   (1s,4r)-4-(2-(1-((R)-2-(1,3,4-oxadiazol-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenyl)cyclohexan-1-ol;-   (1r,4r)-4-(2-(1-((R)-2-(1,3,4-oxadiazol-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenyl)cyclohexan-1-ol;-   (R)-2-(6-(4-(2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole;-   2-((R)-6-(4-(2-(((R)-1,4-dioxan-2-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole;-   2-((R)-6-(4-(2-(((S)-1,4-dioxan-2-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole;-   (R)-2-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole;-   (R)-2-(6-(4-(3-fluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole;-   (R)-2-(6-(4-(2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole;-   (R)-1-(2-(1-(2-(1,3,4-thiadiazol-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)-2-methylpropan-2-ol;-   (R)-4-(2-(1-(2-(1,3,4-thiadiazol-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)-2-methylbutan-2-ol;-   (R)-5-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)isothiazole;-   (R)-5-(6-(4-(2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,2,4-thiadiazole;-   (R)-1-(2-(1-(2-(1,2,4-thiadiazol-5-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)-2-methylpropan-2-ol;-   (R)-4-(2-(1-(2-(1,2,4-thiadiazol-5-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)-2-methylbutan-2-ol;-   (R)-5-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-3-methyl-1,2,4-thiadiazole;-   (R)-1-(5-fluoro-2-(1-(2-(4-methyloxazol-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)-2-methylpropan-2-ol;-   (R)-2-methyl-1-(2-(1-(2-(4-methyloxazol-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)propan-2-ol;-   (R)-3-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,2,4-oxadiazole;-   (R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane    formate salt;-   (R)-2-methyl-1-(2-(1-(2-(pyrimidin-5-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)propan-2-ol    formate salt;-   (R)-2-methyl-1-(2-(1-(2-(4-methylpyrimidin-5-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)propan-2-ol    formate salt;-   (R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(6-methylpyridin-3-yl)-2-azaspiro[3.4]octane    formate salt;-   (R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(2-methylpyrimidin-5-yl)-2-azaspiro[3.4]octane;-   (R)-2-(5-fluoropyridin-3-yl)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octane;-   (R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(6-methylpyrazin-2-yl)-2-azaspiro[3.4]octane;-   (R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(pyrazin-2-yl)-2-azaspiro[3.4]octane;-   (R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(3-(trifluoromethyl)pyrazin-2-yl)-2-azaspiro[3.4]octane;-   (R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(3-methylpyrazin-2-yl)-2-azaspiro[3.4]octane;-   (R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(pyridin-3-yl)-2-azaspiro[3.4]octane;-   (R)-2-(6-methylpyridin-3-yl)-6-(4-(2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane;-   (R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(4-methyl-1,3,5-triazin-2-yl)-2-azaspiro[3.4]octane;-   (R)-2-(6-chloropyridazin-3-yl)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octane;-   (R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(pyridazin-3-yl)-2-azaspiro[3.4]octane;-   (R)-6-(4-(5-chloro-2-methoxyphenyl)piperidin-1-yl)-2-(pyridazin-4-yl)-2-azaspiro[3.4]octane;-   (R)-6-(4-(2-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,5-triazin-2-yl)-2-azaspiro[3.4]octane;-   (R)-2-(3,6-dichloropyridazin-4-yl)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octane;-   (R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(pyridazin-4-yl)-2-azaspiro[3.4]octane;-   (R)-2-methyl-1-(2-(1-(2-(3-methylpyrazin-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)propan-2-ol;-   (R)-1-(2-(1-(2-(1,3,5-triazin-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)-2-methylpropan-2-ol;-   (R)-6-(4-(5-fluoro-2-methoxyphenyl)piperidin-1-yl)-2-(pyridazin-4-yl)-2-azaspiro[3.4]octane;-   (R)-6-(4-(3-fluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane;-   (R)-6-(4-(2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-2-(pyridazin-3-yl)-2-azaspiro[3.4]octane;-   (R)-6-(4-(2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-2-(5-methylpyrazin-2-yl)-2-azaspiro[3.4]octane;-   (R)-6-(4-(2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-2-(pyridazin-4-yl)-2-azaspiro[3.4]octane;-   (R)-2-(5-fluoropyridin-3-yl)-6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane;-   (R)-2-(pyrimidin-5-yl)-6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane;-   (R)-2-(6-fluoropyridin-3-yl)-6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane;-   (R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(5-methylpyrazin-2-yl)-2-azaspiro[3.4]octane;-   (R)-(6-(4-(5-fluoro-2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone;-   (R)-(6-(4-(2-(difluoromethoxy)-4-fluorophenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone;-   (R)-(6-(4-(4-fluoro-2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone;-   (R)-(6-(4-(4-fluoro-2-isopropoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone;-   (R)-(6-(4-(2-cyclopropoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone;-   (R)-(6-(4-(2-(2-fluoro-2-methylpropoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone;-   (R)-oxetan-3-yl(6-(4-(2-(thiazol-2-yloxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-3-(2-(1-(2-(oxetane-3-carbonyl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)propanenitrile;-   oxetan-3-yl((R)-6-(4-(2-(((R)-tetrahydrofuran-3-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-(6-(4-(2-isobutoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone;-   (R)-(6-(4-(2-(cyclopentyloxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone;-   (R)-(6-(4-(2-cyclobutoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone;-   (R)-(6-(4-(2-(cyclopropylmethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone;-   (R)-(6-(4-(2-ethoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone;-   (R)-(6-(4-(2-isopropoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone;-   (R)-(6-(4-(2-(2-hydroxy-2-methylpropoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone;-   (R)-(1-fluorocyclopropyl)(6-(4-(2-(pyrimidin-2-ylmethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (S)-(1-fluorocyclopropyl)(6-(4-(2-(pyrimidin-2-ylmethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-(1-fluorocyclopropyl)(6-(4-(2-(2-hydroxyethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (S)-(1-fluorocyclopropyl)(6-(4-(2-(2-hydroxyethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-(6-(4-(2-(cyclopropylmethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (R)-(6-(4-(2-(cyclopropylmethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (R)-1-(2-(2-(1-(2-(1-fluorocyclopropane-1-carbonyl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)ethyl)pyrrolidin-2-one    formate salt;-   (S)-1-(2-(2-(1-(2-(1-fluorocyclopropane-1-carbonyl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)ethyl)pyrrolidin-2-one    formate salt;-   (R)-(1-fluorocyclopropyl)(6-(4-(2-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (S)-(1-fluorocyclopropyl)(6-(4-(2-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-(1-fluorocyclopropyl)(6-(4-(2-((5-methyl-1,3,4-thiadiazol-2-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (S)-(1-fluorocyclopropyl)(6-(4-(2-((5-methyl-1,3,4-thiadiazol-2-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-(6-(4-(2-ethoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (S)-(6-(4-(2-ethoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (R)-(6-(4-(2-(cyclopropylmethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (R)-(6-(4-(2-(cyclopropylmethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (R)-(6-(4-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (S)-(6-(4-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (R)-(1-fluorocyclopropyl)(6-(4-(2-((2-methyloxazol-5-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (S)-(1-fluorocyclopropyl)(6-(4-(2-((2-methyloxazol-5-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-(1-fluorocyclopropyl)(6-(4-(2-((5-methyl-1,3,4-oxadiazol-2-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (S)-(1-fluorocyclopropyl)(6-(4-(2-((5-methyl-1,3,4-oxadiazol-2-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-(1-fluorocyclopropyl)(6-(4-(2-((5-methyl-1,2,4-oxadiazol-3-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (S)-(1-fluorocyclopropyl)(6-(4-(2-((5-methyl-1,2,4-oxadiazol-3-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-(1-fluorocyclopropyl)(6-(4-(2-((5-methyl-1,3,4-oxadiazol-2-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (S)-(1-fluorocyclopropyl)(6-(4-(2-((5-methyl-1,3,4-oxadiazol-2-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-(1-fluorocyclopropyl)(6-(4-(2-((5-methyl-1,2,4-oxadiazol-3-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (S)-(1-fluorocyclopropyl)(6-(4-(2-((5-methyl-1,2,4-oxadiazol-3-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-(1-fluorocyclopropyl)(6-(4-(2-(3,3,3-trifluoropropoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (S)-(1-fluorocyclopropyl)(6-(4-(2-(3,3,3-trifluoropropoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-(1-fluorocyclopropyl)(6-(4-(2-(3-hydroxy-3-methylbutoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (S)-(1-fluorocyclopropyl)(6-(4-(2-(3-hydroxy-3-methylbutoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-(6-(4-(2-(3-hydroxy-3-methylbutoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone;-   (R)-oxetan-3-yl(6-(4-(2-(2-(trifluoromethoxy)ethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-oxetan-3-yl(6-(4-(2-(2-(oxetan-3-yloxy)ethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-(1-fluorocyclopropyl)(6-(4-(2-(3-methoxy-3-methylbutoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (S)-(1-fluorocyclopropyl)(6-(4-(2-(3-methoxy-3-methylbutoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-oxetan-3-yl(6-(4-(2-(3,3,3-trifluoropropoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-(6-(4-(2-(2-methoxy-2-methylpropoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone;-   (R)-oxetan-3-yl(6-(4-(2-((1-(trifluoromethyl)cyclopropyl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-(6-(4-(2-(2,2-difluoroethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone;-   (R)-oxetan-3-yl(6-(4-(2-(2-(oxetan-3-yl)ethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (S)-(6-(4-(5-chloro-2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (R)-(6-(4-(5-chloro-2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (S)-(6-(4-(5-chloro-2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (R)-(6-(4-(5-chloro-2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (S)-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone;-   (R)-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone;-   (S)-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone;-   (R)-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone;-   (S)-(6-(4-(2-(difluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone;-   (R)-(6-(4-(2-(difluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone    citrate salt;-   (S)-(6-(4-(2-(difluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone;-   (R)-(6-(4-(2-(difluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone    citrate salt;-   (S)-oxetan-3-yl(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-oxetan-3-yl(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-(1-fluorocyclopropyl)(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (S)-(1-fluorocyclopropyl)(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-(1-fluorocyclopropyl)(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (S)-(1-fluorocyclopropyl)(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-(6-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (S)-(6-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (R)-(6-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (S)-(6-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (R)-(1-fluorocyclopropyl)(6-(4-(2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (S)-(1-fluorocyclopropyl)(6-(4-(2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-(1-fluorocyclopropyl)(6-(4-(2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (S)-(1-fluorocyclopropyl)(6-(4-(2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-(1-fluorocyclopropyl)(6-(4-(2-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (S)-(1-fluorocyclopropyl)(6-(4-(2-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-(1-fluorocyclopropyl)(6-(4-(2-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (S)-(1-fluorocyclopropyl)(6-(4-(2-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-(6-(4-(5-fluoro-2-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (S)-(6-(4-(5-fluoro-2-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (R)-(6-(4-(5-fluoro-2-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (S)-(6-(4-(5-fluoro-2-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (R)-(6-(4-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (S)-(6-(4-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (R)-(6-(4-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (S)-(6-(4-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (R)-(1-fluorocyclopropyl)(6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (S)-(1-fluorocyclopropyl)(6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-6-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-(5-fluoropyridin-3-yl)-2-azaspiro[3.4]octane;-   (S)-6-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-(5-fluoropyridin-3-yl)-2-azaspiro[3.4]octane;-   (R)-6-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-(5-fluoropyridin-3-yl)-2-azaspiro[3.4]octane;-   (S)-6-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-(5-fluoropyridin-3-yl)-2-azaspiro[3.4]octane;-   (R)-6-(4-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane;-   (S)-6-(4-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane;-   (R)-6-(4-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane;-   (S)-6-(4-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane;-   (R)-6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane;-   (S)-6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane;-   (R)-6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane;-   (S)-6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane;-   (R)-6-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane;-   (S)-6-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane;-   (R)-6-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane;-   (S)-6-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane;-   (S)-2-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)oxazole;-   (R)-2-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)oxazole;-   (S)-2-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)oxazole;-   (R)-2-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)oxazole;-   (R)-2-(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)oxazole;-   (S)-2-(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)oxazole;-   (R)-2-(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)oxazole;-   (S)-2-(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)oxazole;-   (R)-2-(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole;-   (S)-2-(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole;-   (R)-2-(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole;-   (S)-2-(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole;-   (R)-2-(6-(4-(2-(difluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole;-   (S)-2-(6-(4-(2-(difluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole;-   (R)-2-(6-(4-(2-(difluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole;-   (S)-2-(6-(4-(2-(difluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole;-   (R)-5-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,2,4-thiadiazole;-   (S)-5-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,2,4-thiadiazole;-   (R)-5-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,2,4-thiadiazole;-   (S)-5-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,2,4-thiadiazole;-   (R)-(6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (S)-(6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (R)-(6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (S)-(6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (R)-(6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (S)-(6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;-   (R)-(6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone;    and-   (S)-(6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone,    or a pharmaceutically acceptable salt thereof.

In one embodiment, provided herein is a compound selected from the groupconsisting of:

-   (R)-2-(6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole;-   (S)-2-(6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole;-   (R)-(1-fluorocyclopropyl)(6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (S)-(1-fluorocyclopropyl)(6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;-   (R)-2-(pyrimidin-5-yl)-6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane;-   (S)-oxetan-3-yl(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone;    and-   (R)-oxetan-3-yl(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone,    or a pharmaceutically acceptable salt thereof.

In one embodiment, provided herein is a compound selected from the groupconsisting of:

-   (R)-2-(6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole,    having the following structure:

(R)-(1-fluorocyclopropyl)(6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone,having the following structure:

(R)-2-(pyrimidin-5-yl)-6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane,having the following structure:

and(R)-oxetan-3-yl(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone,having the following structure:

or a pharmaceutically acceptable salt thereof.

In one embodiment, provided herein is a pharmaceutical compositioncomprising a compound provided herein or a pharmaceutically acceptablesalt thereof.

6.3. Pharmaceutical Compositions

In one embodiment, provided herein is a pharmaceutical compositioncomprising a compound provided herein, or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier. In anotherembodiment, provided herein is a pharmaceutical composition comprising atherapeutically effective amount of a compound of Formula (I), or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier. In another embodiment, provided herein is apharmaceutical composition comprising a compound of Formula (I), or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier. In a further embodiment, the composition comprisesat least two pharmaceutically acceptable carriers, such as thosedescribed herein. The pharmaceutical composition can be formulated forparticular routes of administration such as oral administration,parenteral administration (e.g., by injection, infusion, transdermal ortopical administration), and rectal administration. Topicaladministration may also pertain to inhalation or intranasal application.The pharmaceutical compositions provided herein can be made up in asolid form (including, without limitation, capsules, tablets, pills,granules, powders or suppositories), or in a liquid form (including,without limitation, solutions, suspensions or emulsions). Tablets may beeither film coated or enteric coated according to methods known in theart. Typically, the pharmaceutical compositions are tablets or gelatincapsules comprising the active ingredient together with one or more ofthe following:

-   -   a) diluents, e.g., lactose, dextrose, sucrose, mannitol,        sorbitol, cellulose and/or glycine;    -   b) lubricants, e.g., silica, talcum, stearic acid, its magnesium        or calcium salt and/or polyethylene glycol; for tablets also    -   c) binders, e.g., magnesium aluminum silicate, starch paste,        gelatin, tragacanth, methylcellulose, sodium        carboxymethylcellulose and/or polyvinylpyrrolidone; if desired    -   d) disintegrants, e.g., starches, agar, alginic acid or its        sodium salt, or effervescent mixtures; and    -   e) absorbents, colorants, flavors and sweeteners.

The pharmaceutical compositions provided herein can be in unit dosage ofabout 1-1000 mg of active ingredient(s) for a subject of about 50-70 kg,or about 1-500 mg or about 1-250 mg or about 1-150 mg or about 0.5-100mg, or about 1-50 mg of active ingredients. The therapeuticallyeffective dosage of a compound or the pharmaceutical composition thereofis dependent on the species of the subject, the body weight, age andindividual condition, the disorder or disease or the severity thereofbeing treated. A physician, clinician or veterinarian of ordinary skillcan readily determine the effective amount of each of the activeingredients necessary to prevent, treat or inhibit the progress of thedisorder or disease.

The above-cited dosage properties are demonstrable in vitro and in vivotests using advantageously mammals, e.g., mice, rats, dogs, monkeys orisolated organs, tissues and preparations thereof. The compoundsprovided herein can be applied in vitro in the form of solutions, e.g.,aqueous solutions, and in vivo either enterally, parenterally,advantageously intravenously, e.g., as a suspension or in aqueoussolution. The dosage in vitro may range between about 10⁻³ molar and10⁻⁹ molar concentrations. A therapeutically effective amount in vivomay range depending on the route of administration, between about0.1-500 mg/kg, or between about 1-100 mg/kg.

6.4. Methods of use

In one embodiment, the compounds provided herein are in free form or inpharmaceutically acceptable salt form and have activity as muscarinic M4receptor agonists. In a specific embodiment, provided herein arecompounds according to Formula (I) in free form or in pharmaceuticallyacceptable salt form having activity as muscarinic M4 receptor agonists.A significant advantage of the compounds provided herein is that theyare highly selective for the M4 receptor, relative to the M1, M2, and M3receptor subtypes and thus are thought to retain their desired activityin the brain but not produce unwanted cholinergic side effects. Themuscarinic activity of the compounds provided herein can be determinedusing the CHRM4 Ca⁺⁺ Flux Assay described in Section 8.2 below.

By virtue of their M4 receptor agonist activity, the compounds providedherein may be useful in the treatment of:

-   -   Psychosis, including psychosis associated with schizophrenia,        schizoaffective disorder, psychotic depression, bipolar disorder        with psychotic features, Alzheimer's Disease, Parkinson's        Disease, post-traumatic stress disorder, and frontotemporal        dementia;    -   Hyperkinetic Movement Disorders, including but not limited to        Tourette's Syndrome, chorea and tardive dyskinesia;    -   Cognitive dysfunction, including but not limited to cognitive        dysfunction associated with schizophrenia, Alzheimer's Disease,        frontotemporal dementia, schizoaffective disorder, and        depression; and/or    -   Substance Use Disorders.

In one embodiment, provided herein is a method of treating a condition,disease or disorder which is treated by a M4 receptor agonist comprisingadministration of a therapeutically effective amount of a compoundaccording to Formula (I) or a pharmaceutically acceptable salt thereofto a subject in need of treatment thereof. In a further embodiment, thecondition, disease or disorder is psychosis, including but not limitedto, psychosis associated with schizophrenia, schizoaffective disorder,psychotic depression, bipolar disorder with psychotic features,Alzheimer's disease, Parkinson's Disease, post-traumatic stressdisorder, and frontotemporal dementia. In a specific embodiment, thepsychosis is associated with Alzheimer's disease.

In another embodiment, provided herein is a method of treating ahyperkinetic movement disorder, such as Tourette's syndrome, chorea ortardive dyskinesia, comprising administration of a therapeuticallyeffective amount of a compound according to Formula (I) or apharmaceutically acceptable salt thereof to a subject in need oftreatment thereof. In some embodiments, the hyperkinetic movementdisorder is associated with schizophrenia, schizoaffective disorder,psychotic depression, bipolar disorder with psychotic features,Alzheimer's disease, or frontotemporal dementia. In specific embodiment,the hyperkinetic movement disorder is associated with Alzheimer'sdisease.

In another embodiment, provided herein is a method of treating cognitivedysfunction, such as cognitive dysfunction associated withschizophrenia, Alzheimer's disease, frontotemporal dementia,schizoaffective disorder, or depression, comprising administration of atherapeutically effective amount of a compound according to Formula (I)or a pharmaceutically acceptable salt thereof to a subject in need oftreatment thereof. In a specific embodiment, the cognitive dysfunctionis associated with Alzheimer's disease.

In another embodiment, provided herein is a method of treating substanceuse disorders comprising administration of a therapeutically effectiveamount of a compound according to Formula (I) or a pharmaceuticallyacceptable salt thereof to a subject in need of treatment thereof.

In one embodiment, provided herein is the use of a compound according toFormula (I) or a pharmaceutically acceptable salt thereof in therapy. Ina further embodiment, the therapy is selected from a condition, diseaseor disorder which is treated by a M4 receptor agonist. In anotherembodiment, the condition, disease or disorder is selected from theafore-mentioned list, suitably psychosis, including but not limited to,psychosis associated with schizophrenia, schizoaffective disorder,psychotic depression, bipolar disorder with psychotic features,Alzheimer's disease, Parkinson's Disease, post-traumatic stressdisorder, and frontotemporal dementia. In a specific embodiment, thepsychosis is associated with Alzheimer's disease

In another embodiment, provided herein is the use of a compoundaccording to Formula (I) or a pharmaceutically acceptable salt thereofin a hyperkinetic movement disorder, such as Tourette's syndrome, choreaor tardive dyskinesia. In some embodiments, the hyperkinetic movementdisorder is associated with schizophrenia, schizoaffective disorder,psychotic depression, bipolar disorder with psychotic features,Alzheimer's disease, or frontotemporal dementia. In specific embodiment,the hyperkinetic movement disorder is associated with Alzheimer'sdisease.

In another embodiment, provided herein is the use of a compoundaccording to Formula (I) or a pharmaceutically acceptable salt thereofin cognitive dysfunction, for example cognitive dysfunction associatedwith schizophrenia, Alzheimer's disease, frontotemporal dementia,schizoaffective disorder, or depression. In a specific embodiment, thecognitive dysfunction is associated with Alzheimer's disease.

In another embodiment, provided herein is the use of a compoundaccording to Formula (I) or a pharmaceutically acceptable salt thereofin substance use disorders.

In another embodiment, provided herein is the use of a compoundaccording to Formula (I) or a pharmaceutically acceptable salt thereoffor the manufacture of a medicament. In a further embodiment, themedicament is for treatment of a condition, disease or disorder which istreated by a M4 receptor agonist. In another embodiment, the condition,disease or disorder is psychosis, including but not limited to,psychosis associated with schizophrenia, schizoaffective disorder,psychotic depression, bipolar disorder with psychotic features,Alzheimer's disease, Parkinson's Disease, post-traumatic stressdisorder, and frontotemporal dementia.

In another embodiment, provided herein is the use of a compoundaccording to Formula (I) or a pharmaceutically acceptable salt thereoffor the manufacture of a medicament for the treatment of a hyperkineticmovement disorder, such as Tourette's syndrome, chorea or tardivedyskinesia. In some embodiments, the hyperkinetic movement disorder isassociated with schizophrenia, schizoaffective disorder, psychoticdepression, bipolar disorder with psychotic features, Alzheimer'sdisease, or frontotemporal dementia. In specific embodiment, thehyperkinetic movement disorder is associated with Alzheimer's disease.

In another embodiment, provided herein is the use of a compoundaccording to Formula (I) or a pharmaceutically acceptable salt thereoffor the manufacture of a medicament for the treatment of cognitivedysfunction, for example cognitive dysfunction associated withschizophrenia, Alzheimer's disease, frontotemporal dementia,schizoaffective disorder, or depression. In a specific embodiment, thecognitive dysfunction is associated with Alzheimer's disease.

In another embodiment, provided herein is the use of a compoundaccording to Formula (I) or a pharmaceutically acceptable salt thereoffor the manufacture of a medicament for the treatment of substance usedisorders.

In another embodiment, provided herein is a compound according toFormula (I) or a pharmaceutically acceptable salt thereof for use in thetreatment of a condition, disease or disorder which is treated by a M4receptor agonist. In a further embodiment, the condition, disease ordisorder is selected from the afore-mentioned list, suitably psychosis,including but not limited to, psychosis associated with schizophrenia,schizoaffective disorder, psychotic depression, bipolar disorder withpsychotic features, Alzheimer's disease, Parkinson's Disease,post-traumatic stress disorder, and frontotemporal dementia. In aspecific embodiment, the psychosis is associated with Alzheimer'sdisease.

In another embodiment, provided herein is a compound according toFormula (I) or a pharmaceutically acceptable salt thereof for use in thetreatment of a hyperkinetic movement disorder, such as Tourette'ssyndrome, chorea or tardive dyskinesia. In some embodiments, thehyperkinetic movement disorder is associated with schizophrenia,schizoaffective disorder, psychotic depression, bipolar disorder withpsychotic features, Alzheimer's disease, or frontotemporal dementia. Inspecific embodiment, the hyperkinetic movement disorder is associatedwith Alzheimer's disease.

In another embodiment, provided herein is a compound of Formula (I) or apharmaceutically acceptable salt thereof for use in the treatment ofcognitive dysfunction, for example cognitive dysfunction associated withschizophrenia, Alzheimer's disease, frontotemporal dementia,schizoaffective disorder, or depression. In a specific embodiment, thecognitive dysfunction is associated with Alzheimer's disease.

In another embodiment, provided herein is a compound of Formula (I) or apharmaceutically acceptable salt thereof for use in the treatment ofsubstance use disorders.

A compound according to Formula (I) or a pharmaceutically acceptablesalt thereof may be administered either simultaneously with, or beforeor after, one or more other therapeutic agents. The compounds accordingto Formula (I) may be administered separately, by the same or differentroute of administration, or together in the same pharmaceuticalcomposition as the other agents. A therapeutic agent is, for example, achemical compound, peptide, antibody, antibody fragment or nucleic acid,which is therapeutically active or enhances the therapeutic activitywhen administered to a subject in combination with a compound providedherein.

In the combination therapies provided herein, a compound according toFormula (I) and the other therapeutic agent may be manufactured and/orformulated by the same or different manufacturers. Moreover, thecompounds provided herein and the other therapeutic may be broughttogether into a combination therapy: (i) prior to release of thecombination product to physicians (e.g., in the case of a kit comprisinga compound provided herein and the other therapeutic agent); (ii) by thephysician themselves (or under the guidance of the physician) shortlybefore administration; (iii) in the patient themselves, e.g., duringsequential administration of a compound provided herein and the othertherapeutic agent.

A compound according to Formula (I) or a pharmaceutically acceptablesalt thereof may be administered with an antipsychotic, suitably afirst-generation antipsychotic such as chlorpromazine (thorazine),haloperidol, mesoridazine, thioridazine, thiothixene, pimozide,fluphenazine or perphenazine, a second-generation antipsychotic such asclozapine, olanzapine, risperidone, quetiapine, aripiprazole, asenapine,brexpiprazole, cariprazine, iloperidone, ziprasidone, lurasidone,pimavanserin or paliperidone. In certain embodiments, a compoundaccording to Formula (I) or a pharmaceutically acceptable salt thereofmay be administered with an antipsychotic and a cholinesteraseinhibitor, such as donepizil, rivastigmine tartrate, galantamine,tacrine or memantine. In certain embodiments, a compound according toFormula (I) or a pharmaceutically acceptable salt thereof may beadministered with an antipsychotic and a mood stabilizer, such aslithium, divalproex sodium, carbamazepine or lamotrigine.

A compound according to Formula (I) or a pharmaceutically acceptablesalt thereof may be administered with an antidepressant, suitably aselective serotonin reuptake inhibitor such as sertraline, fluoxetine,fluvoxamine, escitalopram, paroxetine or citalopram, aserotonin-norepinephrine reuptake inhibitor such as vortioxetine,venlafaxine, desvenlafaxine, milnacipran, duloxetine or levomilnacipran,a phenylpiperazine antidepressant such as nefazodone, vilazodone ortrazodone, reversible monoamine oxidase inhibitors such as moclobemide,melatonin agonists such as agomelatine, serotonin agonists such asmirtazapine, N-methyl-D-aspartate receptor antagonists such asesketamine and ketamine, and monoamine oxidase inhibitors such astranylcypromine, phenelzine, transdermal selegiline or isocarboxazid.

A compound according to Formula (I) or a pharmaceutically acceptablesalt thereof may be administered in conjunction with standardizepsychological treatment, for example at individual or group therapy. Inanother embodiment, a compound according to Formula (I) or apharmaceutically acceptable salt thereof may be administered inconjunction with psychosocial or behavioral therapy either throughstandardized psychological treatment or through computer-assistance. Incertain embodiment, the computer-assistance is by means of a digital orelectronic device such as online tools, smartphones, laptops, tablets,wireless devices or health Apps.

In a further embodiment, provided herein is a method of treatment of acondition, disease or disorder which is treated with a M4 receptoragonist comprising administration of a therapeutically effective amountof a compound according to Formula (I) or a pharmaceutically acceptablesalt thereof and an antipsychotic to a subject in need of treatmentthereof. In certain embodiments, provided herein is a method oftreatment of a condition, disease or disorder which is treated with a M4receptor agonist comprising administration of a therapeuticallyeffective amount of a compound according to Formula (I) or apharmaceutically acceptable salt thereof, an antipsychotic, and acholinesterase inhibitor to a subject in need of treatment thereof. Incertain embodiments, provided herein is a method of treatment of acondition, disease or disorder which is treated with a M4 receptoragonist comprising administration of a therapeutically effective amountof a compound according to Formula (I) or a pharmaceutically acceptablesalt thereof, an antipsychotic, and a mood stabilizer to a subject inneed of treatment thereof.

In a further embodiment, provided herein is a method of treatment of acondition, disease or disorder which is treated with a M4 receptoragonist comprising administration of a therapeutically effective amountof a compound according to Formula (I) or a pharmaceutically acceptablesalt thereof and an antidepressant to a subject in need of treatmentthereof.

In a further embodiment, provided herein is the use of a compoundaccording to Formula (I) or a pharmaceutically acceptable salt thereofin a condition, disease or disorder which is treated with a M4 receptoragonist, wherein the use is combined with an antipsychotic. In certainembodiments, provided herein is the use of a compound according toFormula (I) or a pharmaceutically acceptable salt thereof in acondition, disease or disorder which is treated with a M4 receptoragonist, wherein the use is combined with an antipsychotic and acholinesterase inhibitor. In certain embodiments, provided herein is theuse of a compound according to Formula (I) or a pharmaceuticallyacceptable salt thereof in a condition, disease or disorder which istreated with a M4 receptor agonist, wherein the use is combined with anantipsychotic and a mood stabilizer.

In a further embodiment, provided herein is the use of a compoundaccording to Formula (I) or a pharmaceutically acceptable salt thereofin a condition, disease or disorder which is treated with a M4 receptoragonist, wherein the use is combined with an antidepressant.

In a further embodiment, provided herein is the use of a compoundaccording to Formula (I) or a pharmaceutically acceptable salt thereoffor the manufacture of a medicament for treatment of a condition,disease or disorder which is treated with a M4 receptor agonist whereinthe use is combined with an antipsychotic. In certain embodiments,provided herein is the use of a compound according to Formula (I) or apharmaceutically acceptable salt thereof for the manufacture of amedicament for treatment of a condition, disease or disorder which istreated with a M4 receptor agonist wherein the use is combined with anantipsychotic and a cholinesterase inhibitor. In certain embodiments,provided herein is the use of a compound according to Formula (I) or apharmaceutically acceptable salt thereof for the manufacture of amedicament for treatment of a condition, disease or disorder which istreated with a M4 receptor agonist wherein the use is combined with anantipsychotic and a mood stabilizer.

In a further embodiment, provided herein is the use of a compoundaccording to Formula (I) or a pharmaceutically acceptable salt thereoffor the manufacture of a medicament for treatment of a condition,disease or disorder which is treated with a M4 receptor agonist whereinthe use is combined with an antidepressant.

In a further embodiment, provided herein is the use of a compoundaccording to Formula (I) or a pharmaceutically acceptable salt thereofin a condition, disease or disorder which is treated with a M4 receptoragonist, wherein the use is combined with computer-assisted psychosocialor behavioral therapy.

In a further embodiment, provided herein is a method for the treatmentof a condition, disease or disorder which is treated with a M4 receptoragonist comprising administration of a therapeutically effective amountof a compound according to Formula (I) or a pharmaceutically acceptablesalt thereof in conjunction with computer-assisted psychosocial orbehavioral therapy.

In a further embodiment, provided herein is the use of a compoundaccording to Formula (I) or a pharmaceutically acceptable salt thereoffor the manufacture of a medicament for treatment of a condition,disease or disorder which is treated by a M4 receptor agonist whereinthe use is combined computer-assisted psychosocial or behavioraltherapy.

6.5. Methods of Making

The compounds provided herein may be made by a variety of methods,including standard chemistry. Suitable synthetic routes are depicted inthe schemes below.

The compounds provided herein may be prepared by methods known in theart of organic synthesis as set forth in part by the following syntheticschemes. In the schemes described below, it is well understood thatprotecting groups for sensitive or reactive groups are employed wherenecessary in accordance with general principles or chemistry. Protectinggroups are manipulated according to standard methods of organicsynthesis (see T. W. Greene and P. G. M. Wuts, “Protective Groups inOrganic Synthesis,” Third edition, Wiley, New York 1999). These groupsare removed at a convenient stage of the compound synthesis usingmethods that are readily apparent to those skilled in the art. Theselection processes, as well as the reaction conditions and order oftheir execution, shall be consistent with the preparation of compoundsprovided herein.

Those skilled in the art will recognize if a stereocenter exists in thecompounds provided herein. Accordingly, the compounds provided hereininclude both possible stereoisomers and includes not only racemiccompounds but the individual enantiomers and/or diastereomers as well.When a compound provided herein is desired as a single enantiomer ordiastereomer, it may be obtained by stereospecific synthesis or byresolution of the final product or any convenient intermediate.Resolution of the final product, an intermediate, or a starting materialmay be effected by any suitable method known in the art. See, forexample, “Stereochemistry of Organic Compounds” by E. L. Eliel, S. H.Wilen, and L. N. Mander (Wiley-Interscience, 1994).

The compounds provided herein can be prepared according to the sequenceshown in Scheme 1 below.

In Scheme 1, aldehyde 1 can be alkylated with benzyl bromide to generateprotected aldehyde 2, which can then be allylated withallyltrimethylsilane with a Lewis acid such as ytterbium chloride togive the bis-allylated compound 4. The two vinyl groups can be oxidizedwith an oxidant such as ozone and in the subsequent presence of ahydride source such as sodium borohydride a diol such as compound 5 canbe generated. The diol can then be activated with tosyl chloride togenerate the active diol 6, which can react with an amine, such as amine7, in the presence of a base such as potassium phosphate to givetertiary amine 8. This compound can be deprotected in the presence of anacid such as trifluoroacetic acid to generate a free amine, such asamine 9. The free amine can react with a heteroaryl halide underBuchwald-Hartwig or nucleophilic aromatic substitution conditions toyield a heteroaryl compound such as 11. Alternatively, the heteroarylgroup can contain an ethyl ester such as in 10, which can then behydrolyzed with an aqueous base such as lithium hydroxide and thendecarboxylated with an acid such as hydrochloric acid to give thedecarboxylated heteroaryl 10. The phenol can then be deprotected such asby hydrogen and palladium catalysis to yield a free phenol such as 12,which can then be alkylated with a halide or tosylate to give compoundssuch as 13.

Alternatively, compounds provided herein can be prepared as depicted inScheme 2 below.

In Scheme 2, the free amine 9 can react with the bromo-oxadiazole 14 inthe presence of a base such as potassium phosphate to generateoxadiazole 15. The benzyl group can subsequently be deprotected withhydrogen and palladium catalysis to yield a phenol such as 16 which canfurther react with an alkyl halide or tosylate to give substitutedphenols such as 17. The ethyl group can then be hydrolyzed with anaqueous base such as lithium hydroxide and the resulting acid can bedecarboxylated with an acid such as hydrochloric acid to generatemono-substituted oxadiazoles such as 18.

Alternatively, compounds provided herein can be prepared as shown inScheme 3 below.

In Scheme 3, compounds such as 8 from Scheme 1 can be deprotected withhydrogen and palladium catalysis to generate free phenols such 19 thatcan be further elaborated with an alkyl halide or tosylate to yield asubstituted phenol such as 20. The amine can then be deprotected with anacid such as trifluoroacetic acid to yield a free amine such as 21 thatcan react with a heteroaryl halide under Buchwald-Hartwig ornucleophilic aromatic substitution conditions to give a heteroaryl suchas 23. Alternatively, free amine 21 can react with a heteroaryl halidealso substituted with an ethyl ester to produce a compound such as 22.The ethyl ester can then be hydrolyzed with an aqueous base such aslithium hydroxide and the resulting acid can be decarboxylated with anacid such as hydrochloric acid to generate examples such as 23.

Alternatively, compounds provided herein can be prepared as shown inScheme 4 below.

In Scheme 4, compounds such as 21 from Scheme 3 can react withheteroaryls containing multiple halogens to give substituted heteroarylssuch as 24. These halogens can also be reduced with hydrogen underpalladium catalysis to yield de-halogenated heteroaryls such as 25.

In Scheme 5, an aldehyde such as 26 can react with a phosphorus reagentsuch as 27 to generate an unsaturated ester such as 28. The ester canthen react with diethyl malonate to generate a triester such as 23 whichcan be decarboxylated with an acid such as hydrochloric acid or sodiumchloride to generate a di-acid or di-ester such as 30. A diol such as 31can then be generated with a reducing agent such as lithium borohydrideor borane and the diol can be activated with tosyl chloride. Exposingdi-tosylate 32 to an amine such as 7 in the presence of a base such aspotassium phosphate can then yield a tertiary amine such as 33. The arylbromide 33 can then be used as a substrate in a Suzuki-Miyaura crosscoupling with a boronic ester such as 34 in the presence of palladiumcatalyst and base. An unsaturated ring such as 35 can then be reducedsuch as with hydrogen and palladium catalyst to yield a saturated ringsuch as 36. The amine can then be deprotected with an acid such astrifluoroacetic acid and the resulting free amine 37 can react with aheteroaryl halide under Buchwald-Hartwig or nucleophilic aromaticsubstitution conditions to yield examples such as 39. Alternatively,free amines such as 31 can react with a heteroaryl halide containing anethyl ester to give an ester substituted heteroaryl such as 38. Theester can then be hydrolyzed with an aqueous base such as lithiumhydroxide and the resulting acid can be decarboxylated to yield examplessuch as 39.

Alternatively, compounds provided herein can be prepared as shown inScheme 6 below.

In Scheme 6, a boronic acid such as 40 can react with an unsaturatedlactone such as 41 under rhodium catalysis to give a saturated lactonesuch as 42. The lactone can then be reduced with a reducing agent suchas lithium borohydride to yield a diol such as 43. Diols such as 43 canthen intersect with the synthetic route shown in Scheme 1.

Alternatively, compounds provided herein can be prepared as shown inScheme 7 below.

In Scheme 7, free phenols such as 19 can be activated as triflates suchas 44. Triflates such as 44 can be transformed into boronic acid such aswith tetrahydroxydiboron with palladium catalysis and the resultingboronic acid can react with vinyl bromides such as 45 to formunsaturated compounds such as 46. Compounds such as 46 can be reducedwith hydrogen in the presence of palladium to generate saturatedcompounds such as 47 which can be deprotected with an acid such as TFA.The free amine generated can then react with a heteroaryl halide underBuchwald-Hartwig or nucleophilic aromatic substitution conditions togenerate examples such as 50. Alternatively, the amine can react with aheteroaryl halide that contains an ethyl ester to generate an ester suchas 49. The ester can then be hydrolyzed with an aqueous base such aslithium hydroxide and the resulting acid can then be decarboxylated withan aqueous acid such as HCl to give examples such as 50.

In Scheme 8, aryl triflates such as 44 can be activated withtetrahydroxydiboron with palladium catalysis and then react withheteroaryl bromides in the presence of palladium to generate heteroarylcompounds such as 51. The amine can then be deprotected with an acidsuch as TFA to generate free amines such as 52 that can react with aheteroaromatic halide under Buchwald-Hartwig or nucleophilic aromaticsubstitution conditions to generate examples such as 54. Alternatively,the amine can react with a heteroaromatic halide that contains an ethylester to yield esters such as 53. The ester can then be hydrolyzed withan aqueous base such as lithium hydroxide and the resulting acid can bedecarboxylated with an acid such as HCl to give examples such as 54.

Alternatively, compounds provided herein can be prepared as shown inScheme 9 below.

In Scheme 9, an aryl bromide such as 33 can be reacted with a cycloalkylboronic acid such as 55 to give unsaturated rings such as 56. Thealcohol can then be deprotected with a fluoride source such astetrabutylammonium fluoride to give free alcohols such as 57 and theolefin can then be reduced with hydrogen and palladium catalysis to givesaturated rings such as 58. The amine can then be deprotected with anacid such as trifluoroacetic acid and the resulting free amine 59 canreact with a heteroaromatic halide to give examples such as 61.Alternatively, the amine can react with a heteroaromatic halide thatcontains an ester to give esters such as 60. The ester can then behydrolyzed with an aqueous base such as lithium hydroxide and theresulting acid can then be decarboxylated with an acid such as HCl togive examples such as 61.

Alternatively, compounds provided herein can be prepared as shown inScheme 10.

In Scheme 10, an intermediate with a hydrogen at the five position suchas 62 can be chlorinated with a reagent such as CMBG in the presence ofHCl to give chlorinated aryl rings such as 63. The Boc group can then beremoved to give free amines such as 64 and the free amine can then reactwith a halogen containing heteroaromatic under Buchwald-Hartwig ornucleophilic aromatic substitution conditions to give examples such as66. Alternatively, the amine can react with a heteroaromatic containingan ethyl ester to generate esters such as 65. The ester can then behydrolyzed by an aqueous base such as lithium hydroxide and theresulting acid can be decarboxylated with an acid such as HCl to giveexamples such as 66.

Alternatively, compounds provided herein can be prepared as shown inScheme 11.

In Scheme 11, dibromo compounds such as 67 can be combined with nitrilessuch as 68 to generate oxadiazoles such as 69. These can be combinedwith free amines such as 21 to yield bromo oxadiazoles such 70. Thebromine can then be removed with a reducing agent such as sodiumborohydride to yield examples such as 71.

Alternatively, compounds provided herein can be prepared as shown inScheme 12 below.

In Scheme 12, free amines such as 21 can be reacted with an acid in thepresence of an amide bond forming reagent such as TBTU and a base suchas DIPEA to generate amides such as 72. Alternatively, compoundsprovided herein can be prepared as shown in Scheme 13 below.

In Scheme 13, protected amines such as 19 can be deprotected by an acidsuch as TFA and the resulting amines such as 73 can react with an acidin the presence of an amide bond forming reagent such as TBTU and a basesuch as DIPEA to generate amides such as 74. The free phenol can then bealkylated with an alkyl halide or tosylate to generate examples such as75.

Alternatively, compounds provided herein can be prepared as shown inScheme 14 below.

In Scheme 14, aryl bromides such as 76 can react with vinyl pinacolesters such as 77 under Suzuki-Miyaura conditions to generateunsaturated piperidines such as 78. The olefin can be reduced and thebenzyl group can then be removed with hydrogen and palladium catalyst togenerate phenols such as 79. The amine can then be deprotected with anacid such as TFA to generate free amines such as 80. Concurrently,amines such as 81 can be deprotected with an acid such as TFA and theresulting free amine 82 can react with an acid in the presence of anamide bond forming reagent such as TBTU and a base such as DIPEA togenerate amides such as 83. Free amines such as 80 can then react withketones such as 83 in the presence of a Lewis acid such as zinc chlorideand a reducing agent such as sodium cyanoborohydride to generatetertiary amines such as 84. The phenol can then be alkylated togenerated substituted phenols such as 85 and the individual enantiomerssuch as 88 and 89 can then be resolved through chiral SFC.Alternatively, the individual enantiomers of phenols such as 84 can beseparated using chiral SFC to generate the individual enantiomers suchas 86 and 87 and the free phenol in compounds such as this can reactwith an alkyl halide or alkyl tosylate to generate single enantiomerssuch as 88 and 89.

Alternatively, compounds provided herein can be prepared as show inScheme 15 below.

In Scheme 15 aryl bromides such as 90 can react with pinacol boronicesters such as 77 under Suzuki-Miyaura conditions to generateunsaturated piperidines such as 91. The benzyl group can be reduced withhydrogen and palladium catalysis to generate free phenols such as 92 andthe phenol can react with an alkyl halide or alkyl tosylate or alcoholunder Mitsunobu conditions to generate substituted phenols such as 95.Alternatively, aryl bromides such as 93 can be reacted with a pinacolboronic ester such as 77 under Suzuki-Miyaura conditions to generateunsaturated piperidines such as 94. The olefin can be reduced withhydrogen and palladium catalysis to give compounds such as 95 which canbe deprotected with an acid such as TFA to generate free amines such as96. The amine can react with ketones such as 81 with a reducing agentsuch as sodium triacetoxyborohydride and a de-hydrating agent such as 4Amolecular sieves to generate tertiary amines such as 97. The amine canthen be deprotected with an acid such as TFA to generate free aminessuch as 98. The free amine can react with a heteroaromatic halide underBuchwald-Hartwig or nucleophilic aromatic substitution conditions togenerate heteroaryls such as 99. These compounds can then be resolvedinto individual enantiomers such as 100 and 101 using chiral SFC.Alternatively, free amines such as 98 can react with an acid in thepresence of an amide bond forming reagent such as TBTU and a base suchas DIPEA to generate amides such as 102. The individual enantiomers suchas 103 and 104 can then be resolved with chiral SFC.

Alternatively, compounds provided herein can be prepared as described inScheme 16 below.

In Scheme 16, aryl bromides such as 105 can react with ketones such as106 in the presence of an organometallic such as iso-propyl magnesiumbromide to yield tertiary alcohols such as 107. The aryl chloride canthen react with pinacol boronic esters such as 77 under Suzuki-Miyauraconditions to yield unsaturated piperidines such as 108. The olefin canthen be reduced with hydrogen and palladium catalysis to yieldpiperidines such as 109 and the amine can be deprotected with an acidsuch as TFA to generate free amines such as 110. The amine can thenreact with ketones such as 83 in the presence of a dehydrating agentsuch as 4A molecular sieves and a reducing agent such as sodiumtriacetoxy borohydride to yield racemic tertiary amines such as 111. Theindividual enantiomers 112 and 113 can then be resolved with chiral SFC.

Alternatively, compounds provided herein can be prepared as shown inScheme 17 below.

In Scheme 17, aryl iodides such as 114 can react with pinacol boronicesters such as 77 under Suzuki-Miyaura conditions to generateunsaturated piperidines such as 115. The aryl bromide can then reactwith pinacol boronic esters such as 34 under Suzuki-Miyaura conditionsto generate unsaturated rings such as 118. Alternatively, aryl iodidessuch as 116 can react with pinacol esters such as 34 underSuzuki-Miyaura conditions to yield unsaturated rings such as 117. Thearyl bromide can then react with pinacol boronic esters such as 77 underSuzuki-Miyaura conditions to generate unsaturated piperidines such as118. The olefin can then be reduced with hydrogen and palladiumcatalysis to generate saturated piperidines such as 119 which can bedeprotected with an acid such as TFA to generate free amines such as120. The amine can then react with ketones such as 83 in the presence ofa dehydrating agent such as 4A molecular sieves and a reducing agentsuch as sodium triacetoxy borohydride to yield tertiary amines such as121. The individual enantiomers 122 and 123 can then be resolved withchiral SFC. Alternatively, compounds provided herein can be described asdescribed in Scheme 18 below.

In Scheme 18, boronic acid 124 can be combined with an unsaturatedlactone under rhodium catalysis to generate saturated lactones such as125. The lactone can then be reduced to a diol such as 126 using areducing agent such as lithium borohydride and the resulting diol can beactivated as a bis-tosylate as 127. The activated diol can then reactwith a primary amine such as 128 in the presence of a based such aspotassium phosphate to give compounds such as 129.

7. INCORPORATION BY REFERENCE

The entire disclosure of each of the patent documents and scientificarticles cited herein are incorporated by reference for all purposes.

8. EXAMPLES

The present disclosure is further illustrated by the following examples,which are intended to be illustrative only and not limiting in any way.It is to be understood that resort may be had to various otherembodiments, modifications, and equivalents thereof which may suggestthemselves to those skilled in the art without departing from the spiritof the present disclosure and/or scope of the appended claims.

8.1. Synthesis of Intermediates and Examples

Abbreviations used are those conventional in the art or the following:

Å angstrom(s)AcOH acetic acidATP adenosine triphosphateAUC area under curveBINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl)BOC tert-ButyloxycarbonylBrettPhos Pd G3[(2-Di-cyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate methanesulfonatetBu tert-butyl

C Celsius

cAMP cyclic adenosine mono-phosphate

CBMG 2-Chloro-1,3-bis(methoxycarbonyl)guanidine

CDI carbonyldiimidazoleDAST Diethylaminosulfur trifluorideDCE 1,2 dichloroethaneDCM dichloromethane

DEA Diethylamine

DEAD Diethyl azodicarboxylate

DIEA/DIPEA N, N-Diisopropylethylamine

DIAD Diisopropyl azodicarboxylateDME 1,2-dimethoxyethane

DMEM Dulbecco's Modified Eagle Medium DMF N,N-dimethylformamide

DMSO dimethylsulfoxide

DPBS Dulbecco's Phosphate Buffered Saline

EtOAc Ethyl acetateEtOH Ethyl alcohol

FBS Fetal Bovine Serum

FCC flash column chromatographyg gram(s)h/hr hour(s)HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide HexafluorophosphateHBSS Hanks' balanced salt solutionHBTU 1-[bis(dimethylamino)methylene]-1Hbenzotriazoliumhexafluorophosphate(1-) 3-oxideHEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid)HOBt 1-hydroxy-7-azabenzotriazoleHPLC high pressure liquid chromatography

Hz Hertz

IPA isopropyl alcoholJ coupling constantkg kilogram(s)L liter(s)LCMS liquid chromatography and mass spectrometry

Me Methyl MHz Megahertz

mm millimeter(s)mM millimolarMTBE methyl tert-butyl etherMS mass spectrometrymin minute(s)mg milligram(s)mL milliliter(s)mmol millimole(s)m/z mass to charge rationm nanometer(s)nM nanomolarNMR nuclear magnetic resonancePd palladiumPd/C, Pd—C palladium on carbonPd(dba)₂ bis(dibenzylideneacetone)palladium(0)Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium(0)Pd(dppf)Cl₂ dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)PE petroleum etherppm parts per millionpsi pounds per square inchrac racemicRB round bottomrpm revolutions per minuteRT room temperatureRt retention timeRuPhos Pd G2Chloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)SCX strong cation exchangeSFC Supercritical fluid chromatographyTBTU 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethylaminiumtetrafluoroborateTC tissue cultureTEA triethylamineTFA trifluoroacetic acidTHE tetrahydrofuranTPGS-750-M DL-α-Tocopherol methoxypolyethylene glycol succinate solutionμL microliter(s)μM micromolarUPLC ultra performance liquid chromatographyUV ultravioletXantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxantheneXphos Pd G2Chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)

General Procedures:

Where no preparative route is described, the material is commerciallyavailable. Commercial reagents were used without additional purificationunless otherwise stated. Room temperature (RT) is approximately 20-25°C. ¹H NMR were recorded at 400 MHz on a Bruker instrument and processedwith mNOVA. Chemical shifts are reported as parts per million (ppm)relative to tetramethylsilane and coupling constants (J) are reported inHertz. Abbreviations for multiplicity are: s=singlet, d=doublet,t=triplet, q=quartet, dd=doublet of doublet, dt=doublet of triplets,br=broad.

LCMS Method 1:

Instrument: Waters Acquity UPLC, photodiode array detector; Column:AcQuity UPLC BEH C₁₈ 1.7 μm, 21×30 mm; 2 min run time, 2% solvent B from0 to 0.1 min, 2→98% solvent B:solvent A from 0.1 to 1.8 min, 98% solventB for 0.2 min. Solvents: Solvent A=0.1% formic acid in water (v/v),solvent B=0.1% formic acid in acetonitrile (v/v). Injection volume 2-5uL; UV detection array 210-400, Mass detection 120-1250 (electrosprayionization); column at 50° C.; flow rate 1.0 mL/min.

LCMS Method 2:

Instrument: Waters Acquity UPLC, photodiode array detector; Column:AcQuity UPLC BEH C₁₈ 1.7 μm 21×50 mm; 2 min run time, 2% solvent B from0 to 0.1 min, 2→98% solvent B:solvent A from 0.1 to 1.8 min, 98% solventB for 0.2 min. Solvents: Solvent A=5 mM ammonium hydroxide in water,solvent B=5 mM ammonium hydroxide in acetonitrile. Injection volume 2-5uL; UV detection array 210-400, Mass detection 120-1250 (electrosprayionization); column at 50° C.; flow rate 1.0 mL/min.

LCMS Method 3:

Instrument: Waters Acquity UPLC, photodiode array detector; ColumnAcQuity UPLC BEH C₁₈ 1.7 μm 21×30 mm; 5.2 min run time, 2→98% solventB:solvent A from 0 to 5.15 min, 98% solvent B from 5.15 to 5.20 min.Solvents: Solvent A=0.1% formic acid in water (v/v), solvent B=0.1%formic acid in acetonitrile (v/v). Injection volume 2-5 uL; UV detectionarray 210-400, Mass detection 120-1600; column at 50° C., flow rate 1.0mL/min.

LCMS Method 4:

Instrument: Waters Acquity UPLC, photodiode array detector; ColumnAcQuity UPLC BEH C₁₈ 1.7 μm 21×30 mm; 5.2 min run time, 2→98% solventB:solvent A from 0 to 5.15 min, 98% solvent B from 5.15 to 5.20 min.Solvents: Solvent A=5 mM ammonium hydroxide in water, solvent B=5 mMammonium hydroxide in acetonitrile). Injection volume 2-5 uL; UVdetection array 210-400, Mass detection 120-1600; column at 50° C., flowrate 1.0 mL/min.

LCMS Method 5:

Instrument: Agilent 1200 LC/G1956A, diode array detector; Column:Chromolith Flash Cis, 1.6 micron 2×25 mm; 1.5 minute run time, 5-95%solvent B: solvent A from 0→1.2 minutes and then 95% solvent B from1.21→1.5 minutes. Solvents: Solvent A=0.0³⁷5% TFA in Water (v/v),Solvent B=0.01875% TFA in Acetonitrile (v/v). Injection volume 2-5 uL;UV detection 220 and 254 nM, Mass detection 100-1000 (electrosprayionization); column at 50° C.; Flow rate 1.5 mL/min.

LCMS Method 6:

Instrument: SHIMADZU LCMS-2020, photo diode array detector; Column:Kinetex EVO Cis, 5 uM, 1×30 mm; 1.55 minute run time, 5→95% solventB:solvent A from 0→1.20 minutes and then 95% solvent B from 1.21 minutesto 1.55 minutes. Solvents: Solvent A=0.025% NH₄OH in water/v), SolventB=acetonitrile. Injection volume 2-5 uL; UV detection 220 and 254 nM,Mass detection 100-100 (electrospray ionization); column at 40° C.; Flowrate 1.5 mL/min.

Intermediate 1A: 3-(2-(benzyloxy)phenyl)pentane-1,5-diylbis(4-methylbenzenesulfonate)

Step 1: 4-(2-(benzyloxy)phenyl)tetrahydro-2H-pyran-2-one

Potassium hydroxide (3.95 g, 70.3 mmol) in water (17.50 mL) was addeddropwise to a solution of [RhCl(COD)]2 (0.347 g, 0.703 mmol),(2-(benzyloxy)phenyl)boronic acid (commercially available, 22.46 g, 98mmol) and 5,6-dihydro-2H-pyran-2-one (commercially available, 6.06 mL,70.3 mmol) in 1,4-dioxane (175 mL) at 0° C. over a period of 2 mins. Thetemperature of reaction was then raised to 35° C. and stirred for 16 h.The reaction was diluted with EtOAc (200 mL) and 2M HC (50 mL). Theaqueous solution was separated and back extracted with EtOAc (50 mL).The combined organic layers were dried over MgSO₄ and the solvent wasremoved under reduced pressure. The crude mixture was then purified byFCC (0→60% EtOAc/heptanes) to yield the title compound (19.49 g, 68.3mmol).

LCMS: Rt=1.03 min (LCMS Method 1); MS m/z 283.5 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.49-7.27 (m, 5H), 7.20 (ddd, J=14.8, 7.5, 1.8Hz, 2H), 7.05 (dd, J=8.1, 1.2 Hz, 1H), 6.99-6.89 (m, 1H), 5.13 (s, 2H),4.49-4.27 (m, 2H), 3.71-3.50 (m, 1H), 2.85 (dd, J=17.2, 6.4 Hz, 1H),2.68 (dd, J=17.2, 9.8 Hz, 1H), 2.10 (m, 2H).

Step 2: 3-(2-(benzyloxy)phenyl)pentane-1,5-diol

Lithium aluminum hydride (76 mL, 76 mmol, 1M in THF) was added to astirred solution of 4-(2-(benzyloxy)phenyl)tetrahydro-2H-pyran-2-one(19.49 g, 69.0 mmol) in anhydrous THE (400 mL) at 0° C. and then thereaction mixture was stirred for 2 h at 0° C. The reaction was quenchedby water (10 mL) at −5° C. until gas production ceased and then asolution of NaOH (25 g) in water (25 mL) was portion-wise added to themixture at 0° C. Na₂SO₄ (300 g) was next added to the reaction mixtureand was stirred for 60 min. The mixture was filtered and the solvent wasremoved under reduced pressure. The crude product was purified by FCC(0-10% MeOH/DCM) to yield the title compound (19.3 g, 64.1 mmol).

LCMS: Rt=0.85 min (LCMS Method 1); MS m/z 287.3 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 7.51-7.31 (m, 5H), 7.26-7.16 (m, 2H),7.07-6.95 (m, 2H), 5.11 (s, 2H), 3.61-3.35 (m, 5H), 1.92 (m, 4H), 1.66(s, 2H).

Step 3: 3-(2-(benzyloxy)phenyl)pentane-1,5-diylbis(4-methylbenzenesulfonate)

To the solution of 3-(2-(benzyloxy)phenyl)pentane-1,5-diol (19.31 g,67.4 mmol) and triethylamine (41.4 mL, 297 mmol) in MeCN (40 mL) at −5°C. was added TsCl (28.3 g, 148 mmol) and DMAP (0.824 g, 6.74 mmol).After addition, the reaction was stirred at RT for 16 h. The solvent wasremoved under reduced pressure. The crude product was dissolved in DCM(200 mL) and washed with water (25 mL) and brine (25 mL) then dried overNa₂SO₄ and filtered. The DCM was removed under reduced pressure and thecrude was purified by FCC (0→50% EtOAc/heptanes) to yield the titlecompound.

LCMS: Rt=1.37 min (LCMS Method 2).

¹H NMR (400 MHz, CDCl₃) δ 7.74-7.63 (m, 4H), 7.46-7.33 (m, 5H), 7.30 (s,4H), 7.20-7.13 (m, 1H), 6.99-6.72 (m, 3H), 5.00 (s, 2H), 4.01-3.61 (m,4H), 3.15 (m, 1H), 2.45 (s, 6H), 2.03 (m, 2H), 1.89 (m, 2H).

Intermediate 1B: 3-(2-(benzyloxy)-5-fluorophenyl)pentane-1,5-diylbis(4-methylbenzenesulfonate)

Step 1: 4-(2-(benzyloxy)-5-fluorophenyl)tetrahydro-2H-pyran-2-one

(5-(benzyloxy)-2-fluorophenyl)boronic acid (commercially available, 24g, 98 mmol), 5,6-dihydro-2H-pyran-2-one (commercially available, 6.06mL, 70.3 mmol) and [RhCl(COD)]2 (0.5 g, 1.014 mmol), were dissolved indioxane (180 mL) and cooled to −10° C. Then, potassium hydroxide (4.38g, 78 mmol) was dissolved in water (17.8 mL) and added to the dioxanesolution dropwise over 10 min. The reaction was then warmed to 35° C.and stirred for 2 hours. The reaction was neutralized with 1M HCl (to pH3), then concentrated under vacuum to remove the dioxane. The residuewas then diluted with water (50 mL) and extracted with EtOAc (3×300 mL)the organics were combined and concentrated under vacuum. The crude waspurified by FCC (0→100% EtOAc/heptanes) to yield the title compound(19.65 g, 78 mmol).

LCMS: RT=1.07 min (LCMS Method 2); MS m/z 301.4 [M+H]⁺.

Step 2: 3-(2-(benzyloxy)-5-fluorophenyl)pentane-1,5-diol

Lithium aluminum hydride (31.2 mL, 71.8 mmol, 2M THF) was added to astirred solution of4-(2-(benzyloxy)-5-fluorophenyl)tetrahydro-2H-pyran-2-one (19.6 g, 65.3mmol) in dry THE (384 mL) at 0° C. The reaction mixture was stirred for2 h at −5° C. under N₂. The reaction was quenched by H₂O (10 mL) at −5°C. until gas production ceased and then a solution of NaOH (25 g) inwater (25 mL) was portion-wise added to the mixture at 0° C. Na₂SO₄ (300g) was added to the reaction mixture and was stirred for 60 min. Themixture was filtered and the solvent was removed under reduced pressure.The crude product was purified by FCC (0-10% MeOH/DCM) to yield thetitle compound (17.8 g, 55.6 mmol).

LCMS: Rt=0.90 min (LCMS Method 2); MS m/z 304.4 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 7.51-7.31 (m, 5H), 7.01-6.81 (m, 3H), 5.06 (s,2H), 3.59-3.47 (m, 3H), 3.46-3.31 (m, 2H), 2.06-1.89 (m, 4H), 1.81-1.73(m, 2H).

Step 3: 3-(2-(benzyloxy)-5-fluorophenyl)pentane-1,5-diylbis(4-methylbenzenesulfonate)

3-(2-(benzyloxy)-5-fluorophenyl)pentane-1,5-diol (17.8 g, 58.5 mmol) andTEA (35.9 mL, 257 mmol) were dissolved in MeCN (200 mL) and cooled to−5° C. TsCl (24.53 g, 129 mmol) and DMAP (0.714 g, 5.85 mmol) were addedand the reaction was warmed to RT and stirred for 16 h. The solvent wasremoved under reduced pressure. The crude product was dissolved in DCM(300 mL) and washed with water (1×25 mL) and brine (1×25 mL), dried overNa₂SO₄, filtered and concentrated. The crude product was purified by FCC(0→50% EtOAc/heptanes) to yield the title compound (22.8 g, 37.2 mmol).

LCMS Rt=1.37 min (LCMS Method 2); MS m/z 630.4 [M+NH_(4]) ⁺.

Intermediate 1D: 3-(2-bromophenyl)pentane-1,5-diylbis(4-methylbenzenesulfonate) Wuxi

Step 1: triethyl 2-(2-bromophenyl)propane-1,1,3-tricarboxylate

Na (27.04 g, 1180 mmol) was added to EtOH (1.5 L) in several batchesunder nitrogen and then the reaction was stirred at 25° C. until thesolid was completely dissolved. Then diethyl malonate (188 g, 1180 mmol)was added to the EtOH solution and the resulting mixture was stirred at25° C. for 0.5 hr. Next, ethyl (E)-3-(2-bromophenyl)acrylate 3 (J. Med.Chem. 1990, 33, 909-918) 150 g, 0.588 mol) was added to the mixturewhich was then stirred for 16 hours at 80° C. The solution was thenconcentrated and the residue was purified by FCC (2-20% EtOAc/PE) toyield the title intermediate (133 g, 0.320 mol) as a colorless oil.

¹H NMR (400 MHz, CDCl₃) δ 7.57-7.48 (m, 1H), 7.30-7.18 (m, 2H),7.11-7.00 (m, 1H), 4.48-4.36 (m, 1H), 4.24-4.13 (m, 2H), 4.07-3.90 (m,5H), 3.00-2.84 (m, 2H), 1.26-1.20 (m, 3H), 1.13-0.99 (m, 6H).

Step 2: diethyl 3-(2-bromophenyl)pentanedioate

To a solution of triethyl 2-(2-bromophenyl)propane-1,1,3-tricarboxylate(133 g, 320 mmol) in DMSO (500 mL) was added NaCl (56 g, 960 mmol) andwater (17 g, 960 mmol). The mixture was stirred at 160° C. for 6 hours.The reaction mixture was then quenched with water (500 mL) and extractedwith MTBE (3×500 mL). The combined organic phases were washed with brine(500 mL) dried over sodium sulfate, filtered and concentrated to givethe title intermediate (105 g, 306 mmol) as a yellow oil which was usedin the next step without further purification.

¹H NMR (400 MHz, CDCl₃) δ 7.58-7.55 (m, 1H), 7.28-7.25 (m, 2H),7.10-7.08 (m, 1H), 4.20-4.15 (m, 1H), 4.09-4.04 (m, 4H), 2.79-2.70 (m,4H), 1.19-1.15 (m, 6H).

Step 3: 3-(2-bromophenyl)pentane-1,5-diol

To a suspension of LiAlH₄ (29 g, 765 mmol) in THE (800 mL) cooled to 0°C. was added dropwise a solution of diethyl3-(2-bromophenyl)pentanedioate (105 g, 306 mmol) in THE (200 mL).Following the addition, the reaction was warmed to 25° C. and stirredfor 2 hours. The reaction mixture was then added dropwise to a solutionof 2 N HCl (2L) and then extracted with EtOAc (3×500 mL). The combinedorganic extracts were washed with brine (500 mL), dried over sodiumsulfate, filtered, and concentrated. The residue was purified by FCC(10-100% EtOAc/DCM (3:1)/PE) to yield a white solid. The solid wastriturated with EtOAc (100 mL) and filtered and washed with cold EtOAc(2×50 mL) to afford the title intermediate (47.2 g, 182 mmol) as a whitesolid.

¹H NMR (400 MHz, CD₃OD) δ 7.55-7.53 (m, 1H), 7.33-7.32 (m, 2H),7.10-7.06 (m, 1H), 3.47-3.39 (m, 5H), 1.96-1.86 (m, 4H).

Step 5: 3-(2-bromophenyl)pentane-1,5-diyl bis(4-methylbenzenesulfonate)

3-(2-bromophenyl)pentane-1,5-diol (10.1 g, 39.0 mmol) was dissolved inMeCN (200 mL) and 4-methylbenzene-1-sulfonyl chloride (17.09 g, 90 mmol)and N,N-dimethylpyridin-4-amine (0.476 g, 3.90 mmol) were added. Theresulting solution was cooled to 0° C. and triethylamine (32.4 ml, 234mmol) was added dropwise. The reaction mixture was warmed to RT and thecolorless solution color became brown and then it became turbid. Thereaction mixture was stirred at RT for 5 hours. The reaction mixture wasconcentrated, diluted with DCM (300 mL) and washed with 1N HCl solution(2×50 mL), dried over sodium sulfate, filtered and concentrated underreduced pressure. The crude was purified by FCC (0-50% EtOAc/Heptanes)to obtain a colorless solid as the title compound (21.2 g, 35.9 mmol).

LCMS Rt=1.37 min (LCMS Method 2); MS m/z 586.1 [M+NH₄]+.

¹H NMR (400 MHz, CD₂Cl₂) δ 7.76-7.68 (m, 4H), 7.50 (dd, J=8.0, 1.2 Hz,1H), 7.36 (d, J=8.2 Hz, 4H), 7.28-7.20 (m, 1H), 7.12-7.01 (m, 2H),3.92-3.86 (m, J=10.0, 6.2 Hz, 2H), 3.84-3.78 (m, J=9.9, 7.0 Hz, 2H),3.47-3.31 (m, 1H), 2.47 (s, 6H), 2.04-1.90 (dt, J=13.2, 7.0 Hz, 4H).

Intermediate 1E: 3-(2-(benzyloxy)-4-fluorophenyl)pentane-1,5-diylbis(4-methylbenzenesulfonate)

Step 1: 2-(benzyloxy)-4-fluoro-1-(hepta-1,6-dien-4-yl)benzene

A 250 mL round bottom flask was charged with2-(benzyloxy)-4-fluorobenzaldehyde (commercially available, 23.90 g, 104mmol) followed by nitromethane (250 mL). Then ytterbium(III) chloride(7.25 g, 26.0 mmol) was added to the reaction and the mixture wasstirred for 15 min at RT. After 15 min of stirring, allyltrimethylsilane(41.2 mL, 260 mmol) was slowly added over 5 min. The mixture was stirredovernight at RT. The reaction was concentrated and the crude product waspurified by FCC (0→30% EtOAc/heptanes) to yield the title compound as aclear, colorless oil (22.64 g, 72.6 mmol).

LCMS: Rt=1.43 min (LCMS Method 1).

¹H NMR (400 MHz, CDCl₃) δ 7.38-7.19 (m, 5H), 6.97 (dd, 1H), 6.61-6.47(m, 2H), 5.57 (m, 2H), 4.95 (s, 2H), 4.90-4.78 (m, 4H), 3.19 (t, 1H),2.29 (m, 4H).

Step 2: 3-(2-(benzyloxy)-4-fluorophenyl)pentane-1,5-diol

2-(benzyloxy)-4-fluoro-1-(hepta-1,6-dien-4-yl)benzene (22.64 g, 76 mmol)was dissolved in MeOH (450 mL) and cooled to −78° C. Next, ozone wasbubbled through the reaction mixture for 120 min over which time thereaction turned a pale purple color. Nitrogen was then bubbled throughthe reaction for 20 min and it was then warmed to 0° C. and NaBH4 (28.9g, 764 mmol) was added to the reaction portion wise over 4 h and thereaction was then stirred for 16 hours at RT. The reaction was thenpoured into DCM and sat NH₄C₁ was added and the mixture was stirred atRT for 1 h. The organic layer was separated and washed with water andbrine then dried over Na₂SO₄ and filtered. The solvent was removed underreduced pressure. The resulting product (15.22 g, 50.0 mmol) was takenforward without further purification.

LCMS: Rt=0.90 min (LCMS Method 1); MS m/z 305.2 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 7.36-7.22 (m, 6H), 7.03 (m, 1H), 6.64-6.57 (m,2H), 4.95 (s, 2H), 3.42 (m, 2H), 3.31 (m, 2H), 1.92-1.81 (m, 2H),1.79-1.64 (m, 2H).

Step 3: 3-(2-(benzyloxy)-4-fluorophenyl)pentane-1,5-diylbis(4-methylbenzenesulfonate)

3-(2-(benzyloxy)-4-fluorophenyl)pentane-1,5-diol (6.96 g, 22.87 mmol)was dissolved in MeCN (150 mL) and TEA (13.63 mL, 98 mmol) was added andthe reaction was cooled to 0° C. The reaction was incubated for 10 minand then TsCl (9.59 g, 50.3 mmol) and DMAP (0.559 g, 4.57 mmol) wereadded. The reaction was slowly warmed to RT and stirred overnight. Thereaction was then diluted with water and extracted with DCM. Thecombined organic layers were dried over magnesium sulfate, filtered andconcentrated. The residue was then purified by FCC (0→60%EtOAc/heptanes) to yield the title compound (8.91 g, 14.54 mmol).

LCMS: Rt=1.35 min (LCMS Method 1); MS m/z 630.3 [M+NH₄]⁺.

¹H NMR (400 MHz, CDCl₃) δ 7.68-7.61 (m, 4H), 7.42-7.32 (m, 5H), 7.27 (m,4H), 6.57 (dd, J=10.9, 2.4 Hz, 1H), 6.46 (td, J=8.3, 2.4 Hz, 1H), 4.93(s, 2H), 3.90-3.80 (m, 2H), 3.74 (ddd, J=9.8, 8.1, 6.1 Hz, 2H), 3.08(dt, J=9.7, 4.9 Hz, 1H), 2.43 (s, 6H), 1.98 (m, 3H), 1.92-1.80 (m, 2H).

Intermediate 1F: 3-(2-bromo-5-fluorophenyl)pentane-1,5-diylbis(4-methylbenzenesulfonate)

Step 1: triethyl 2-(2-bromo-5-fluorophenyl)propane-1,1,3-tricarboxylate

Sodium metal (25.25 g, 1.10 mol) was added to EtOH (1.5 L) in severalbatches under N₂ gas flow and the reaction mixture was stirred at 25° C.until the solid dissolved. Next, diethyl malonate (176 g, 1.10 mol) wasadded to the mixture and stirred at 25° C. for 30 minutes, ethyl(E)-3-(2-bromo-5-fluorophenyl)acrylate (150 g, 0.55 mol; Preparation inOrg. Biomol. Chem. 2012, 10, 3655-3661) was added to the reactionmixture and the reaction was stirred for 16 hours at 80° C. The reactionmixture was then concentrated and the residue was purified by FCC (2-10%EtOAc/petroleum ether) to the title intermediate (140 g, 323 mmol) as acolorless oil.

¹H NMR (400 MHz, CDCl₃) δ 7.51 (dd, J=5.5, 8.8 Hz, 1H), 7.02 (dd, J=3.1,9.8 Hz, 1H), 6.83 (m, 1H), 4.38 (q, J=7.4 Hz, 1H), 4.24-4.18 (m, 2H),4.10-3.97 (m, 4H), 3.92 (m, 1H), 2.91 (d, J=7.1 Hz, 2H), 1.23 (t, J=7.2Hz, 3H), 1.13 (t, J=7.2 Hz, 6H).

Step 2: 3-(2-bromo-5-fluorophenyl)pentanedioic acid

Triethyl 2-(2-bromo-5-fluorophenyl)propane-1,1,3-tricarboxylate (140 g,323 mmol) was dissolved in HCl (36.5%, 1L) and was stirred at 100° C.for 48 hr. The solution was the concentrated to give the titleintermediate (109 g, 358 mmol, crude) as light yellow solid that wasused without further purification.

¹H NMR (400 MHz, DMSO-d₆) δ 7.61 (m, 1H), 7.47-7.28 (m, 1H), 7.20-6.98(m, 1H), 3.91-3.80 (m, 1H), 2.61 (m, 4H).

Step 3: 3-(2-bromo-5-fluorophenyl)pentane-1,5-diol

To a solution of 3-(2-bromo-5-fluorophenyl)pentanedioic acid (105 g,crude) in THE (1000 mL) was dropwise added B₂H₆ (172 mL, 17.2 mmol, 10 Min dimethyl sulfide) at 0° C. The solution was then warmed to RT andstirred for 2 hours. The reaction was cooled to 0° C. and quenched withMeOH (500 mL) and HCl (250 mL, 4M in EtOAc), and the solution was thenconcentrated. The residue was purified by FCC (5-100% EtOAc: DCM(3:1)/petroleum ether) to give the title intermediate (43.3 g, 156 mmol)as a white solid.

¹H NMR (400 MHz, CD₃OD) δ 7.58-7.54 (m, 1H), 7.12 (m, 1H), 6.89 (m, 1H),3.55-3.38 (m, 5H), 2.00-1.79 (m, 4H).

Step 4: 3-(2-bromo-5-fluorophenyl)pentane-1,5-diylbis(4-methylbenzenesulfonate)

3-(2-bromo-5-fluorophenyl)pentane-1,5-diol (5000 mg, 18.04 mmol) to a250 mL rb flask and it was dissolved in MeCN (100 mL). Next, TEA (11.1mL 79 mmol) and DMAP (220 mg, 1.804 mmol) were added and the reactionwas cooled to 0° C. The reaction was incubated for 10 minutes at 0° C.and then tosyl anhydride (13000 mg, 39.8 mmol) was added and thereaction was slowly warmed to RT and the reaction was stirred overnight.The material was next concentrated onto celite for purification by FCC(0-60% EtOAc/heptanes) to yield the title intermediate as a light brownoil (9700 mg, 16.57 mmol).

LCMS: Rt: 1.29 min (LCMS Method 1); MS m/z 604.1 [M+NH₄]⁺.

¹H NMR (400 MHz, CDCl₃) δ 7.75-7.67 (m, 4H), 7.42 (dd, J=8.8, 5.5 Hz,1H), 7.31 (d, J=8.0 Hz, 4H), 6.78 (m, 1H), 6.73-6.62 (m, 1H), 3.88 (m,2H), 3.80 (dt, J=10.1, 6.9 Hz, 2H), 3.34 (s, 1H), 2.44 (s, 6H),2.05-1.93 (m, 2H), 1.89 (bs, 2H).

Intermediate 1G: 3-(2-(benzyloxy)-3-fluorophenyl)pentane-1,5-diylbis(4-methylbenzenesulfonate)

Step 1: 4-(2-(benzyloxy)-3-fluorophenyl)tetrahydro-2H-pyran-2-one

A solution of potassium hydroxide (0.858 g, 15.29 mmol) in water (5.0mL) was added dropwise to a solution of [RhCl(COD)]2 (0.075 g, 0.153mmol), (2-(benzyloxy)-3-fluorophenyl)boronic acid (5.27 g, 21.41 mmol)and 5,6-dihydro-2H-pyran-2-one (1.317 mL, 15.29 mmol) in 1,4-dioxane (50mL) at 0° C. over a period of 2 mins. The reaction solution was thenwarmed to 35° C. and stirred for 16 h. The reaction was diluted withethyl acetate and 2M HCl. The layers were separated and the aqueoussolution was back extracted with ethyl acetate. The combined organicswere dried over MgSO₄ and the solvent was removed under reducedpressure. The residue was then purified by FCC (0-60% EtOAc/heptanes) toyield the title compound (3.71 g, 12.35 mmol).

LCMS: Rt: 2.36 min (LCMS Method 3); MS m/z 301.1 [M+H]⁺.

Step 2: 3-(2-(benzyloxy)-3-fluorophenyl)pentane-1,5-diol

To a stirring solution of4-(2-(benzyloxy)-3-fluorophenyl)tetrahydro-2H-pyran-2-one (3.71 g, 12.35mmol) in THE (60 mL) and MeOH (12 mL) at 0° C., LiBH₄ (538 mg, 24.71mmol) was added. The reaction was then stirred at RT for 16 hours. 100mL of water was then added to the reaction to quench the excess LiBH₄and the organic solvent was removed under reduced pressure. The productwas extracted with DCM, washed with water and dried over MgSO₄. Thesolvent was removed under reduced pressure and the product was usedwithout further purification (3.72 g, 11.61 mmol).

LCMS: Rt: 1.89 min (LCMS Method 3).

¹H NMR (400 MHz, CD₃OD) δ 7.52-7.46 (m, 2H), 7.41-7.30 (m, 3H),7.12-6.97 (m, 3H), 5.05 (s, 2H), 3.40-3.33 (m, 5H), 1.92-1.73 (m, 4H).

Step 3: 3-(2-(benzyloxy)-3-fluorophenyl)pentane-1,5-diylbis(4-methylbenzenesulfonate)

To a solution of 3-(2-(benzyloxy)-3-fluorophenyl)pentane-1,5-diol (1.10g, 3.61 mmol) and triethylamine (2.267 mL, 16.26 mmol) in MeCN (40 mL)was added pTsCl (1.585 g, 8.31 mmol) and DMAP (0.044 g, 0.361 mmol). Thereaction was then stirred for 16 hours and then diluted with water,extracted 3 times with DCM, dried over MgSO₄ and concentrated. Theresidue was purified by FCC (0-50% EtOAc/heptanes) to yield the titlecompound (1.51 g, 2.46 mmol).

LCMS: Rt: 1.37 min (LCMS Method 1).

¹H NMR (400 MHz, CDCl₃) δ 7.72-7.64 (m, 4H), 7.42-7.33 (m, 5H),7.31-7.28 (m, 4H), 7.08-6.84 (m, 2H), 6.75-6.64 (m, 1H), 5.02 (s, 2H),3.83 (m, 2H), 3.72 (m, 2H), 3.18 (p, J=7.5 Hz, 1H), 2.45 (s, 6H), 1.86(m, 4H).

Intermediate 1H: 3-(2-(trifluoromethoxy)phenyl)pentane-1,5-diylbis(4-methylbenzenesulfonate)

Step 1: 4-(2-(trifluoromethoxy)phenyl)tetrahydro-2H-pyran-2-one

(2-(trifluoromethoxy)phenyl)boronic acid (2939 mg, 14.27 mmol),5,6-dihydro-2H-pyran-2-one (1000 mg, 10.19 mmol) andchloro(1,5-cyclooctadiene)rhodium(I) dimer (503 mg, 1.019 mmol) wereadded to a 250 mL round bottom flask and dissolved in dioxane (40 mL).Separately in a 25 mL beaker, KOH (572 mg, 10.19 mmol) was dissolved inwater (5 mL) and this solution was then added dropwise to the dioxanesolution. The reaction was warmed to 35° C. and stirred for 24 hours.The reaction was diluted with EtOAc (100 mL) and washed with 2N HCl(2×25 mL) and water (1×10 mL) and brine (1×10 mL), dried over sodiumsulfate, filtered and concentrated. The crude was then purified by FCC(0-75% EtOAc/heptanes) to afford the title intermediate (1880 mg, 7.22mmol).

LCMS: Rt: 1.95 min (LCMS Method 3) MS m/z 261.0 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.51-7.44 (m, 1H), 7.44-7.28 (m, 3H),4.58-4.39 (m, 2H), 3.75-3.61 (m, 1H), 2.90-2.79 (m, 1H), 2.66 (dd,J=17.4, 10.4 Hz, 1H), 2.18-2.05 (m, 2H).

Step 2: 3-(2-(trifluoromethoxy)phenyl)pentane-1,5-diol

4-(2-(trifluoromethoxy)phenyl)tetrahydro-2H-pyran-2-one (1880 mg, 7.22mmol) was dissolved in THE (60 mL) and MeOH (15 mL) and cooled to 0° C.The reaction was incubated for 10 minutes and then lithium borohydride(315 mg, 14.45 mmol) was added and the reaction was warmed to RT andstirred for 20 hours. The reaction was cooled to 0° C. and then quenchedwith acetone and concentrated and the residue was purified by FCC (0-10%MeOH/DCM) to yield the title compound as a colorless oil (1660 mg, 6.28mmol).

LCMS: Rt: 1.95 min (LCMS Method 3) MS m/z 265.6 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.50-7.37 (m, 1H), 7.37-7.21 (m, 3H),3.48-3.37 (m, 4H), 3.30-3.25 (m, 1H), 2.03-1.77 (m, 4H).

Step 3: 3-(2-(trifluoromethoxy)phenyl)pentane-1,5-diylbis(4-methylbenzenesulfonate)

3-(2-(trifluoromethoxy)phenyl)pentane-1,5-diol (1660 mg, 6.28 mmol) wasdissolve in MeCN (30 mL) and DMAP and TEA (4.3 mL), 31.4 mmol) wereadded and the reaction was cooled to 0° C. and incubated for 10 min.Next, TsCl (2635 mg, 13.82 mmol) was added and the reaction was warmedto RT and stirred for 18 h. The reaction was then concentrated anddissolved in EtOAc and washed with water (3×20 mL) and brine (1×20 mL),dried over sodium sulfate, filtered and concentrated. The residue wasthen purified by FCC (0-40% EtOAc/heptanes) to yield the title compoundas a yellow oil (1437 mg, 2.51 mmol).

LCMS: Rt: 1.95 min (LCMS Method 3) MS m/z 590.7 [M+H₂O]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.73-7.63 (m, 4H), 7.44-7.34 (m, 4H),7.29-7.25 (m, 1H), 7.22-7.13 (m, 3H), 3.89-3.84 (m, 2H), 3.75-3.69 (m,2H), 3.19-3.11 (m, 1H), 2.44 (s, 6H), 1.98-1.77 (m, 4H).

Intermediate 2A: tert-butyl(R)-6-amino-2-azaspiro[3.4]octane-2-carboxylate hydrochloride

tert-butyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate (200 g, 0.887 mol),isopropylamine hydrochloride (845 g, 8.84 mol) and pyridoxal phosphate(10 g, 0.040 mmol) were added to a 10 L reactor and suspended in DMSO(800 mL) and 0.1M borate buffer (pH 9.0, 6200 mL). AminotransferaseATA412 (Codexis) was dissolved in 0.1 M borate buffer (400 mL) and addedto the DMSO solution. The flask containing the enzyme was washed with 0.μM borate buffer (400 mL) and this was added to the DMSO solution. Thiswash step was repeated with 0.1 M borate buffer (200 mL). The reactionwas incubated at 40° C. with nitrogen bubbling through the solutionuntil the ketone was consumed as judged by LCMS. The reaction was thencooled to 26° C. and citric acid was added until the solution pH reached4.88. DCM (1.5 L) was added and the solution was filtered throughmicrocrystalline cellulose. The phases were separated and the aqueousphase was added back to the reactor and NaCl (1200 g, 20.5 mol) wasadded and the pH was adjusted to 9.9 with 32% NaOH solution. The aqueouslayer was extracted with DCM (3×2 L) and concentrated. The residue wasdissolved in EtOAc (1.5 L) and washed with brine (2×100 mL). The organiclayer was concentrated and the residue was dissolved in EtOAc (1.0 L)and filtered to remove NaCl and enzyme residue. The EtOAc layer was thenconcentrated and the residue was dissolved in EtOAc (0.87 L) and HCl inEtOAc (2M, 390 mL) was added over 1 hour. The solution was stirred for 2hours and then filtered and washed with EtOAc to yield the titleintermediate (133.9 g, 0.510 mol).

LCMS: Rt: 1.65 min (LCMS Method 4) MS m/z 227.7 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 3.92-3.81 (m, 2H), 3.77 (q, J=8.3 Hz, 2H),3.61 (p, J=7.6 Hz, 1H), 2.40 (dd, J=13.8, 8.1 Hz, 1H), 2.19-2.07 (m,1H), 2.07-1.89 (m, 2H), 1.81 (dd, J=13.8, 7.4 Hz, 1H), 1.71-1.58 (m,1H), 1.43 (s, 9H).

Intermediate 2B: 2-azaspiro[3.4]octan-6-one

To a solution of tert-butyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate(15.69 g, 69.6 mmol) in DCM (60 mL) was added TFA (30 mL). The resultingsolution was stirred at room temperature for 2 hours. It wasconcentrated to give a white solid which was taken on to the next stepwithout purification. A 100% yield was assumed in the next step.

LCMS: Rt: 0.17 min (LCMS Method 1) MS m/z 126.2 [M+H]⁺.

Intermediate 2C:2-(1-fluorocyclopropanecarbonyl)-2-azaspiro[3.4]octan-6-one

To a solution of 2-azaspiro[3.4]octan-6-one (Intermediate 2B, 16.7 g,35.7 mmol) in DCM (50 mL) was added DIPEA (46.6 mL, 267 mL). Thereaction was stirred for 5 min and then the solvent was removed and DMF(20 mL) was added. Concurrently, 1-fluorocyclopropanecarboxylic acid(4.10 g 37.4 mmol) was dissolved in DMF (20 mL) and HATU (14.37 g, 37.8mmol) was added. The reaction was stirred for 30 minutes and then DMFsolution containing 2-azaspiro[3.4]octan-6-one was added and thereaction was stirred for 16 hr. Next, sat NaHCO₃ was added (300 mL) andthe solution was extracted with EtOAc (3×500 mL). The combined organiclayers were washed with brine and concentrated. The crude was thenpurified by FCC (0-70% EtOAc/heptanes) to yield the title compound (6.98g, 29.7 mmol).

LCMS: Rt: 0.58 min (LCMS Method 2) MS m/z 212.2 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 4.50-4.36 (m, 2H), 4.07-3.90 (m, 2H), 2.53 (s,2H) 2.36-2.21 (m, 4H), 1.35-1.18 (m, 4H).

Intermediate 2D: 2-(oxetane-3-carbonyl)-2-azaspiro[3.4]octan-6-one

Oxetane-3-carboxylic acid (3.15 g, 30.9 mmol) and carbonyl diimidazole(5.68 g, 35.0 mmol) were suspended in dioxane (103 mL) and the reactionwas stirred at 80° C. for 4 hours. DMF (10 mL) was then added and thereaction was stirred for an additional hour at 80° C. for 1 hour. Thereaction was then cooled to room temperature. 2-azaspiro[3.4]octan-6-one(Intermediate 2B, 3.33 g, 20.60 mmol) was added by spatula. DMF (6 mL)was added to rinse the spatula and imidazole (0.701 g, 10.30 mmol) wasadded and the reaction was stirred overnight. The reaction wasconcentrated and purified by FCC (0→10% MeOH/DCM). The isolated compoundcontained DMF, so the residue was purified a second time by FCC (0→10%MeOH/DCM) to afford the title intermediate (1.583 g, 7.57 mmol) as anoff-white solid.

LCMS: Rt: 0.37 min (LCMS Method 1), MS m/z 210.1 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 4.98-4.90 (m, 2H), 4.90-4.81 (m, 1H), 4.77 (m,2H), 3.97 (dd, J=17.4, 7.3 Hz, 3H), 3.83 (m, 1H), 2.49 (d, J=4.6 Hz,2H), 2.38-2.29 (m, 2H), 2.29-2.19 (m, 2H).

Intermediate 2E:(R)-(6-amino-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone

Step 1: tert-butyl(R)-6-(((benzyloxy)carbonyl)amino)-2-azaspiro[3.4]octane-2-carboxylate

To a stirring suspension of tert-butyl(R)-6-amino-2-azaspiro[3.4]octane-2-carboxylate hydrochloride(Intermediate 2A, 1 g, 3.81 mmol) in DCM (5 mL) at −5° C., DIPEA (2.0mL, 11.42 mmol) was added. The reaction was stirred for 5 min and thenN-(benzyloxycarbonyloxy)succinimide (1.043 g, 4.19 mmol) was then addedand the reaction was stirred at RT for 3 hr. The reaction was washedwith 1M HCl, sat NaHCO₃, water and brine then dried over Na₂SO₄. Thesolvent was removed under reduced pressure. This gave the titleintermediate, which was used without further purification (1.35 g, 3.37mmol).

LCMS: Rt: 1.10 min (LCMS Method 1), MS m/z 261.5 [M-Boc+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.39-7.22 (m, 5H), 5.05 (s, 2H), 4.00-3.87 (m,1H), 3.77 (m, 4H), 2.19 (dd, J=13.5, 7.5 Hz, 1H), 1.97 (m, 2H), 1.77 (m,2H), 1.59-1.47 (m, 1H), 1.42 (s, 9H).

Step 2: benzyl (R)-(2-azaspiro[3.4]octan-6-yl)carbamate

To a stirring solution of tert-butyl(R)-6-(((benzyloxy)carbonyl)amino)-2-azaspiro[3.4]octane-2-carboxylate(1.35g, 3.75 mmol) in DCM (15 mL), TFA (5.0 mL) was added. The reaction wasstirred at RT for 1 hr. The reaction was concentrated and the crudeproduct was dissolved in DCM and washed with 2M NaOH, until the aqueouslayer was >pH12. The organic layer was then dried over magnesiumsulfate, filtered and concentrated to yield the title intermediate thatwas used without purification (962 mg, 3.51 mmol).

LCMS: Rt: 0.60 min (LCMS Method 1), MS m/z 261.2 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.44-7.21 (m, 5H), 5.05 (d, J=4.3 Hz, 2H),3.89 (p, J=7.1 Hz, 1H), 3.67-3.45 (m, 4H), 2.23 (dd, J=13.3, 7.4 Hz,1H), 2.05-1.63 (m, 4H), 1.57-1.39 (m, 1H).

Step 3: benzyl(R)-(2-(oxetane-3-carbonyl)-2-azaspiro[3.4]octan-6-yl)carbamate

To a stirring solution of oxetane-3-carboxylic acid (127 mg, 1.056 mmol)in DMF (2.0 mL), TBTU (462 mg, 1.440 mmol) was added. This was stirredfor 15 min at RT and then this mixture was added to a stirring solutionof benzyl (R)-(2-azaspiro[3.4]octan-6-yl)carbamate (250 mg, 0.960 mmol)and DIPEA (0.839 mL, 4.80 mmol) in DCM (10 mL). The reaction was thenstirred at RT for 16 hr. The reaction was diluted with DCM and washedwith water, brine, dried over MgSO₄, filtered and concentrated. Thecrude product was then purified by FCC (0-100% EtOAc/heptanes) to yieldthe title compound (225 mg, 0.621 mmol).

LCMS: Rt: 1.63 min (LCMS Method 4), MS m/z 345.3 [M+H]⁺.

Step 4: (R)-(6-amino-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone

To a stirring solution of benzyl(R)-(2-(oxetane-3-carbonyl)-2-azaspiro[3.4]octan-6-yl)carbamate (225 mg,0.653 mmol) in ethanol (10 mL), Pd/C (139 mg, 0.131 mmol) was added. Thereaction was stirred under a balloon of hydrogen for 16 hr. The catalystwas filtered and the solvent was removed under reduced pressure to givethe title intermediate which was used without further purification (128mg, 0.609 mmol).

LCMS: Rt: 0.17 min (LCMS Method 1), MS m/z 211.4 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 4.77 (dd, J=8.1, 2.1 Hz, 4H), 4.09-3.74 (m,5H), 3.39-3.32 (m, 1H), 2.21 (m, 1H), 2.06-1.91 (m, 2H), 1.85 (m, 1H),1.61 (m, 1H), 1.53-1.37 (m, 1H).

Intermediate 3A: tert-butyl(R)-6-(4-(2-(benzyloxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate

tert-butyl (R)-6-amino-2-azaspiro[3.4]octane-2-carboxylate (Intermediate2A, 1.06 g, 4.04 mmol), 3-(2-(benzyloxy)phenyl)pentane-1,5-diylbis(4-methylbenzenesulfonate) (Intermediate 1A, 2.40 g, 4.04 mmol), andpotassium phosphate (2.74 g, 12.7 mmol) were suspended in acetonitrile(27 mL), and the reaction was stirred at 80° C. for 3 days. The reactionwas cooled, concentrated, diluted with ethyl acetate (100 mL), filtered,and the filtrate was concentrated. The residue was purified by FCC (0-5%MeOH(10% NH₄OH)/DCM) to afford the title intermediate (1.7 g, 3.5 mmol)as a white foamy solid.

LCMS: Rt: 1.42 min (LCMS Method 2) MS m/z 477.1 [M+H]⁺.

Intermediate 3B: tert-butyl(R)-6-(4-(2-bromophenyl)piperidin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate

3-(2-bromophenyl)pentane-1,5-diyl bis(4-methylbenzenesulfonate)(Intermediate 1D, 21.2 g, 35.9 mmol) was dissolved in MeCN (200 mL) andtert-butyl (R)-6-amino-2-azaspiro[3.4]octane-2-carboxylate (Intermediate2A, 12.20 g, 39.4 mmol) and K₃PO₄ (24.36 g, 115 mmol) were added. Theround bottom flask was fitted with a reflux condenser and the resultingsuspension was stirred at 94° C. for 36 hours. The reaction mixture wasconcentrated under reduced pressure, and the residue was diluted withEtOAc and the organic phase was washed with water and brine. The organiclayer was dried over sodium sulfate, filtered and concentrated underreduced pressure. The residue was then purified by FCC (0-6% MeOH/DCM)and further by a second round of FCC (0-20% EtOH (20% NH₃ inMeOH)/heptanes). The title compound was isolated as a beige oil (14.8 g,35.9 mmol).

LCMS: Rt: 1.42 min (LCMS Method 2) MS m/z 451.4 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.54 (d, J=8.0 Hz, 1H), 7.32 (d, J=4.4 Hz,2H), 7.09 (dt, J=8.7, 4.5 Hz, 1H), 3.91-3.65 (m, 4H), 3.16 (m, 2H), 3.04(m, 1H), 2.77-2.60 (m, 1H), 2.16 (m, 3H), 2.04-1.82 (m, 5H), 1.73 (m,3H), 1.63-1.50 (m, 1H), 1.43 (s, 9H).

The following compounds in Table 1 were prepared using a similarprocedure and the relevant starting materials:

TABLE 1 Intermediates 3C to 3F Retention time (min) and ExpectedObserved Intermediate Structure Method Mass Mass 3C

1.42 LCMS Method 2 495.3 [M + H]⁺ 495.5 [M + H]⁺ 3D

0.78 LCMS Method 2 467.2 [M + H]⁺ 469.1 [M + H]⁺ 3E

1.92 LCMS Method 3 495.3 [M + H]⁺ 495.6 [M + H]⁺ 3F

3.59 LCMS Method 4 495.3 [M + H]⁺ 495.4 [M + H]⁺

Intermediate 4A:(R)-6-(4-(2-(benzyloxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane

tert-butyl(R)-6-(4-(2-(benzyloxy)phenyl)piperidin-1l-yl)-2-azaspiro[3.4]octane-2-carboxylate(Intermediate 3A, 2.00 g, 4.20 mmol) was dissolved in DCM (30 mL), andTFA (10 mL) was added. The reaction was stirred at RT for 1 hour,concentrated under reduced pressure and the residue was dissolved in DCMand washed with a 1 M solution of NaOH until the combined aqueousextracts were basic (pH>8). The organic layer was washed with brinedried with MgSO4, filtered, and concentrated under reduce pressure toafford the title intermediate (1440 mg, 3.82 mmol).

LCMS: Rt: 0.64 min (LCMS Method 1) MS m/z 377.5 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.47-7.27 (m, 5H), 7.25-7.07 (m, 2H),7.03-6.84 (m, 2H), 5.10 (s, 2H), 3.74 (m, 3H), 3.20-2.95 (m, 4H), 2.64(p, J=8.6 Hz, 1H), 2.34-1.65 (m, 12H), 1.53 (dt, J=12.0, 8.5 Hz, 1H).

The following compounds in Table 2 were prepared using a similarprocedure and the relevant starting materials:

TABLE 2 Intermediates 4B to 4X Retention time (min) and ExpectedObserved Intermediate Structure Method Mass Mass 4B

0.56 LCMS Method 1 395.2 [M + H]⁺ 395.4 [M + H]⁺ 4C

0.46 LCMS Method 1 359.3 [M + H]⁺ 359.3 [M + H]⁺ 4D

0.47 LCMS Method 1 357.3 [M + H]⁺ 357.3 [M + H]⁺ 4E

0.46 LCMS Method 1 345.3 [M + H]⁺ 345.1 [M + H]⁺ 4F

0.45 LCMS Method 1 403.3 [M + H]⁺ 403.3 [M + H]⁺ 4G

0.52 LCMS Method 1 399.3 [M + H]⁺ 399.5 [M + H]⁺ 4H

0.49 LCMS Method 1 371.3 [M + H]⁺ 371.7 [M + H]⁺ 4I

0.54 LCMS Method 1 385.3 [M + H]⁺ 385.4 [M + H]⁺ 4J

0.40 LCMS Method 1 361.2 [M + H]⁺ 361.6 [M + H]⁺ 4K

0.52 LCMS Method 1 373.3 [M + H]⁺ 373.4 [M + H]⁺ 4L

0.47 LCMS Method 1 359.2 [M + H]⁺ 359.4 [M + H]⁺ 4M

0.59 LCMS Method 1 341.3 [M + H]⁺ 341.2 [M + H]⁺ 4N

0.44 LCMS Method 1 343.2 [M + H]⁺ 343.1 [M + H]⁺ 4O

0.52 LCMS Method 1 387.3 [M + H]⁺ 387.3 [M + H]⁺ 4P

0.47 LCMS Method 1 387.3 [M + H]⁺ 387.3 [M + H]⁺ 4Q

0.46 LCMS Method 1 301.2 [M + H]⁺ 301.2 [M + H]⁺ 4R

0.51 LCMS Method 1 373.3 [M + H]⁺ 373.1 [M + H]⁺ 4S

0.63 LCMS Method 1 287.4 [M + H]⁺ 287.3 [M + H]⁺ 4T

0.53 LCMS Method 1 377.3 [M + H]⁺ 377.3 [M + H]⁺ 4U

0.43 LCMS Method 1 319.2 [M + H]⁺ 319.4 [M + H]⁺ 4V

0.52 LCMS Method 1 355.2 [M + H]⁺ 355.3 [M + H]⁺ 4W

0.44 LCMS Method 1 319.2 [M + H]⁺ 319.5 [M + H]⁺ 4X

0.58 LCMS Method 1 347.3 [M + H]⁺ 347.3 [M + H]⁺

Intermediate 4Y:(R)-6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane

(R)-tert-butyl6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate(Intermediate 10A, 87 mg, 0.19 mmol) was dissolved in DCM (1 mL), andTFA (0.02 mL, 0.19 mmol) was added. The reaction was stirred at RT for 2hours, concentrated and the solution was absorbed onto a 1 g SCX column.The column was washed with MeOH and then the product was eluted with 7NNH₃ in MeOH. The ammonia fraction was then concentrated to afford thetitle intermediate (62 mg, 0.18 mmol).

LCMS: Rt: 0.50 min (LCMS Method 1) MS m/z 355.6 [M+H]⁺.

Intermediate 5A:(R)-2-(6-(4-(2-(benzyloxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole

(R)-6-(4-(2-(benzyloxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 4A, 0.79 g, 2.1 mmol), and ethyl5-bromo-1,3,4-oxadiazole-2-carboxylate (556 mg, 2.52 mmol) weredissolved in THE (10 mL), and DIPEA (0.73 mL, 4.2 mmol) was added. Thereaction was stirred at RT for 16 hours, concentrated, and diluted withEtOAc. The solution was washed with water, and concentrated. The residuewas dissolved in a mixture of THE (10 mL), and water (5 mL), then LiOH(0.88 g, 21 mmol) was added. The reaction was stirred at RT for 1 hourand then a 6M solution of HCl (3.5 mL, 21 mmol) was added, and thereaction was stirred for 1 hour. Next, solid sodium carbonate was addedto pH >9, then the solution was concentrated. The residue was dilutedwith EtOAc, washed with brine, and concentrated under reduced pressure.The residue was purified by FCC (0-5% MeOH(10% 7N NH₃)/ethyl acetate) toafford the title intermediate (480 mg, 1.07 mmol).

LCMS: Rt: 1.19 min (LCMS Method 4) MS m/z 445.4 [M+H]⁺.

The following compound in Table 3 was prepared using a similar procedureand the relevant starting materials:

TABLE 3 Intermediate 5B Retention time (min) and Expected ObservedIntermediate Structure Method Mass Mass 5B

1.21 LCMS Method 2 463.3 [M + H]⁺ 463.4 [M + H]⁺

Intermediate 5C: (R)-ethyl5-(6-(4-(2-(benzyloxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole-2-carboxylate

(R)-6-(4-(2-(benzyloxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 4A, 500 mg, 1.33 mmol), ethyl5-bromo-1,3,4-oxadiazole-2-carboxylate (293 mg, 1.33 mmol), andpotassium phosphate (282 mg, 1.33 mmol) were suspended in a mixture of2% aqueous TPGS-750-M (2.4 mL), and THE (0.27 mL). The reaction wasstirred at RT for 16 h, extracted with DCM, and the combined organiclayers were concentrated. The residue was purified by FCC (0-7%MeOH/DCM) to afford the title intermediate (603 mg, 1.17 mmol).

LCMS: Rt: 0.81 min (LCMS Method 1) MS m/z 517.1 [M+H]⁺.

Intermediate 5D:(R)-2-(1-(2-(1,3,4-thiadiazol-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenol

(R)-2-(1-(2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenol (Intermediate4S, 713 mg, 0.722 mmol), 2-bromo-1,3,4-thiadiazole (143 mg, 0.866 mmol)and potassium phosphate (184 mg, 0.866 mmol) were suspended in a mixtureof 2% aqueous TPGS-750-M (1.2 mL) and THE (0.26 mL). The reaction wasstirred at RT for 16 hours, then at 50° C. for 16 hours. The reactionwas then extracted with DCM (3×100 mL), and the combined organic layerswere dried with MgSO₄, filtered and concentrated. The residue waspurified by FCC (0-4% MeOH(10% NH₄OH)/DCM) to afford the titleintermediate (55 mg, 0.15 mmol).

LCMS: Rt: 0.84 min (LCMS Method 2) MS m/z 371.3 [M+H]⁺.

Intermediate 5E:(R)-6-(4-(2-(benzyloxy)phenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane

(R)-6-(4-(2-(benzyloxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 4A, 1.42 g, 3.77 mmol) and 5-bromopyrimidine (0.660 g,4.15 mmol) in dioxane (30 mL) was placed under nitrogen. Pd(dba)₂ (0.217g, 0.377 mmol), xantphos (0.262 g, 0.453 mmol) and 1M NaOtBu in THE(7.54 mL, 7.54 mmol) were added and the reaction was stirred at 80° C.for 16 hrs. The reaction was then cooled to room temperature, filtered,and rinsed through with MeCN and EtOAc. The filtrate was evaporated andthe residue was purified by FCC (0-10% MeOH (1% NH₄OH)/EtOAc) to affordthe title compound (788 mg).

LCMS: Rt: 0.83 min (LCMS Method 1) MS m/z 455.4 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.47 (s, 1H), 8.00 (s, 2H), 7.49-7.27 (m, 5H),7.25-7.10 (m, 2H), 7.07-6.84 (m, 2H), 5.10 (s, 2H), 4.00-3.76 (m, 4H),3.24-3.02 (m, 3H), 2.78 (s, 1H), 2.40-2.12 (m, 3H), 2.11-1.94 (m, 3H),1.91-1.70 (m, 5H), 1.67-1.51 (m, 1H).

Intermediate 6A:(R)-2-(1-(2-(1,3,4-oxadiazol-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenol

(R)-2-(6-(4-(2-(benzyloxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole(Intermediate 5A, 350 mg, 0.787 mmol) was dissolved in MeOH (5 mL), and10% Pd/C (84 mg, 0.079 mmol) was added. The reaction was then stirred atRT under a balloon of hydrogen for 16 hours. The catalyst was filtered,and the filtrate was concentrated to afford the title intermediate (269mg, 0.751 mmol) as a white solid.

LCMS: Rt: 0.84 min (LCMS Method 2) MS m/z 355.2 [M+H]⁺.

The following compounds in Table 4 were prepared using a similarprocedure and the relevant starting materials:

TABLE 4 Intermediates 6B to 6G Retention time (min) and ExpectedObserved Intermediate Structure Method Mass Mass 6B

0.86 LCMS Method 2 373.2 [M + H]⁺ 373.4 [M + H]⁺ 6C

1.08 LCMS Method 2 387.3 [M + H]⁺ 387.4 [M + H]⁺ 6D

1.14 LCMS Method 2 405.3 [M + H]⁺ 405.4 [M + H]⁺ 6E

0.93 LCMS Method 2 427.2 [M + H]⁺ 427.3 [M + H]⁺ 6F

2.57 LCMS Method 3 405.3 [M + H]⁺ 405.8 [M + H]⁺ 6G

2.57 LCMS Method 3 365.2 [M + H]⁺ 365.4 [M + H]⁺

Intermediate 7A: 2-oxaspiro[3.3]heptan-6-yl 4-methylbenzenesulfonate

2-oxaspiro[3.3]heptan-6-ol (2.00 g, 17.5 mmol) was dissolved in DCM (50mL), and DMAP (0.21 g, 1.7 mmol) was added followed by triethylamine(6.1 mL, 44 mmol). The solution was cooled to 0° C., and4-methylbenzene-1-sulfonyl chloride (3.51 g, 18.4 mmol) was added, andthe reaction was stirred for 16 hours at RT. The reaction mixture waswashed with a 1N HCl (1×10 mL), dried over MgSO₄, filtered, andconcentrated under reduced pressure. The residue was purified by FCC(0-80 ethyl acetate/heptane) to afford the title intermediate (4.17 g,14.8 mmol).

LCMS: Rt: 0.86 min (LCMS Method 1) MS m/z 269.3 [M+H].

The following compounds in Table 5 were prepared using a similarprocedure and the relevant starting materials:

TABLE 5 Intermediates 7B to 7M Retention time (min) and ExpectedObserved Intermediate Structure Method Mass Mass 7B

0.82 LCMS Method 2 273.1 [M + H]⁺ 273.0 [M + H]⁺ 7C

0.84 LCMS Method 1 243.1 [M + H]⁺ 243.1 [M + H]⁺ 7D

0.84 LCMS Method 1 273.1 [M + H]⁺ 273.1 [M + H]⁺ 7E

0.91 LCMS Method 1 289.1 [M + H]⁺ Not observed 7F

0.98 LCMS Method 2 285.1 [M + H]⁺ Not observed 7G

1.75 LCMS Method 4 276.1 [M + H]⁺ 276.3 [M + H]⁺ 7H

0.85 LCMS Method 1 261.1 [M + H]⁺ 261.1 [M + H]⁺ 7I

0.86 LCMS Method 1 257.1 [M + H]⁺ 257.2 [M + H]⁺ 7J

1.33 LCMS Method 2 331.1 [M + H]⁺ 331.2 [M + H]⁺ 7K

0.75 LCMS Method 2 284.1 [M + H]⁺ 284.2 [M + H]⁺ 7L

0.79 LCMS Method 2 273.1 [M + H]⁺ 273.4 [M + H]⁺ 7M

1.02 LCMS Method 2 273.1 [M + H]⁺ 273.2 [M + H]⁺

Intermediate 8A: (R)-tert-butyl6-(4-(2-(2-hydroxy-2-methylpropoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate

(R)-tert-butyl6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate(Intermediate 6C, 310 mg, 0.802 mmol), 2,2-dimethyloxirane (289 mg, 4.01mmol), and cesium carbonate (523 mg, 1.60 mmol) were suspended in DMF (8mL), and the reaction was heated at 150° C. in a microwave reactor for45 minutes, diluted with ethyl acetate (100 mL), washed with water (2×25mL), and concentrated under reduced pressure. The residue was purifiedby FCC (0-10% MeOH/DCM) to afford the title intermediate (335 mg, 0.730mmol).

LCMS: Rt: 0.73 min (LCMS Method 1) MS m/z 459.3 [M+H]⁺.

The following compounds in Table 6 were prepared using a similarprocedure and the relevant starting materials:

TABLE 6 Intermediates 8B to 8C Retention time (min) and ExpectedObserved Intermediate Structure Method Mass Mass 8B

1.21 LCMS Method 2 473.3 [M + H]⁺ 473.5 [M + H]⁺ 8C

0.82 LCMS Method 1 477.3 [M + H]⁺ 477.1 [M + H]⁺

Intermediate 8D: tert-butyl(R)-6-(4-(4-fluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate

To a DMF (30 mL) solution of (R)-tert-butyl6-(4-(3-fluoro-2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate(Intermediate 6F, 811 mg, 2.005 mmol) and Cs₂CO₃ (1960 mg, 6.01 mmol)was added oxetan-3-yl 4-methylbenzenesulfonate (503 mg, 2.205 mmol). Theresulting mixture was stirred at 80° C. for 16 hours. The crude wasdiluted with EtOAc and washed with water. The solvent was removed underreduced pressure and the residue was purified by FCC (0-10% MeOH/DCM) toyield the title compound (680 mg, 1.48 mmol).

LCMS: Rt: 2.79 min (LCMS Method 3) MS m/z 461.5 [M+H]⁺.

The following compounds in Table 7 were prepared using a similarprocedure and the relevant starting materials:

TABLE 7 Intermediates 8E to 8N Retentiom time (min) and ExpectedObserved Intermediate Structure Method Mass Mass 8E

1.23 LCMS Method 2 457.3 [M + H]⁺ 457.5 [M + H]⁺ 8F

1.25 LCMS Method 2 445.3 [M + H]⁺ 445.2 [M + H]⁺ 8G

1.26 LCMS Method 2 503.3 [M + H]⁺ 503.4 [M + H]⁺ 8H

1.38 LCMS Method 2 499.4 [M + H]⁺ 499.4 [M + H]⁺ 8I

1.24 LCMS Method 2 471.3 [M + H]⁺ 471.2 [M + H]⁺ 8J

1.28 LCMS Method 2 485.3 [M + H]⁺ 485.2 [M + H]⁺ 8K

2.79 LCMS Method 4 461.3 [M + H]⁺ 461.5 [M + H]⁺ 8L

1.20 LCMS Method 2 443.2 [M + H]⁺ 443.2 [M + H]⁺ 8M

1.21 LCMS Method 2 487.3 [M + H]⁺ 487.2 [M + H]⁺ 8N

1.20 LCMS Method 2 487.3 [M + H]⁺ 487.2 [M + H]⁺

Intermediate 8O: (R)-tert-butyl6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate

(R)-tert-butyl6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate(Intermediate 6C, 1.087 g, 2.81 mmol) was added into a 45 mL falcon tubeand dissolved in THE (25 mL) and methanol (1.0 mL, 24.72 mmol). Ph₃Presin (3 mmol/g, 3.75 g, 11.25 mmol) was added, and the reaction mixturewas cooled to 0° C. DEAD (4000 in toluene, 2.78 mL, 7.03 mmol) was addeddropwise and the reaction was shaken for 24 hours. Additional MeOH (1.0mL, 24.72 mmol) was added and the reaction was shaken for an additional48 hours. Additional DEAD (40% in toluene, 2.78 mL) and Ph₃P resin (3mmol/g, 1.0 g, 3 mmol) was added and the reaction was stirred for anadditional 24 hours. The reaction was then filtered and washed with MeCNand the filtrate was concentrated and purified by FCC (0-8% MeOH (1%NH₄OH)/DCM) to yield the title intermediate.

LCMS: Rt: 1.27 min (LCMS Method 2) MS m/z 401.3 [M+H]⁺.

The following intermediates in Table 8 were prepared in a similar mannerusing the relevant starting materials:

TABLE 8 Intermediates 8P to 8R Retention time (min) and ExpectedObserved Intermediate Structure Method Mass Mass 8P

1.32 LCMS Method 2 419.3 [M + H]⁺ 419.6 [M + H]⁺ 8Q

1.76 LCMS Method 3 447.6 [M + H]⁺ 447.5 [M + H]⁺ 8R

3.17 LCMS Method 4 419.3 [M + H]⁺ 419.8 [M + H]⁺

Intermediate 8S: (R)-tert-butyl6-(4-(2-(difluoromethoxy)-4-fluorophenyl)piperidin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate

(R)-tert-butyl6-(4-(4-fluoro-2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate(Intermediate 6F, 425 mg, 1.051 mmol) was dissolved in a mixture of MeCN(5 mL) and 4M KOH (5.25 mL). The reaction mixture was frozen at −78° C.in a dry ice/acetone bath and diethyl (bromodifluoromethyl)phosphonate(0.373 mL, 2.101 mmol) was added dropwise and the solution was warmed toRT. The reaction mixture was diluted with water and extracted with EtOAc(2×). The combined organics were washed with brine, dried over magnesiumsulfate, filtered, and concentrated. The isolated material (470 mg,1.034 mmol) was used without further purification.

LCMS: Rt: 1.28 min (LCMS Method 2) MS m/z 455.4 [M+H]⁺.

Intermediate 9A: (R)-tert-butyl6-(4-(2-(3,6-dihydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate

(R)-tert-butyl6-(4-(2-bromophenyl)piperidin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate(Intermediate 3B, 153 mg, 0.340 mmol),2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(86 mg, 0.41 mmol),dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) DCM adduct(12 mg, 0.017 mmol) and potassium phosphate (217 mg, 1.02 mmol) weredissolved in a mixture of dioxane (3 mL) and water (0.4 mL). Thereaction mixture was stirred at 100° C. for 2 hours, concentrated, anddiluted with water (200 mL) and extracted with DCM (3×100 mL). Theorganic extracts were dried over sodium sulfate, filtered andconcentrated. The residue was purified by FCC (0-30% EtOAc (20% 7N NH₃in MeOH)/DCM) to afford the title intermediate (132 mg, 0.34 mmol).

LCMS: Rt: 1.28 min (LCMS Method 2) MS m/z 453.3 [M+H]⁺.

The following compound in Table 9 were prepared using a similarprocedure and the relevant starting materials:

TABLE 9 Intermediates 9B to 9E Retention time (min) and ExpectedObserved Intermediate Structure Method Mass Mass 9B

1.26 LCMS Method 2 471.3 [M + H]⁺ 471.7 [M + H]⁺ 9C

1.23 LCMS Method 2 457.3 [M + H]⁺ 457.7 [M + H]⁺ 9D

1.25 LCMS Method 2 439.3 [M + H]⁺ 439.5 [M + H]⁺ 9E

1.78 LCMS Method 2 603.4 [M + Na]⁺ 603.9 [M + Na]⁺

Intermediate 10A: (R)-tert-butyl6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate

(R)-tert-butyl6-(4-(2-(3,6-dihydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate(Intermediate 9A, 132 mg, 0.248 mmol) was dissolved in MeOH (5 mL) and1000 Pd/C (26 mg, 0.025 mmol) was added. The reaction was stirred undera balloon of hydrogen atmosphere for 48 hours and then the solution wasfiltered and concentrated. The residue was purified by FCC (0-6%MeOH/DCM) to afford the title intermediate (87 mg, 0.19 mmol) a yellowfoamy solid. LCMS: Rt: 1.25 min (LCMS Method 2) MS m/z 455.4 [M+H]⁺.

The following compounds in Table 10 were prepared using a similarprocedure and the relevant starting materials:

TABLE 10 Intermediates 10B to 10D Retention time (min) and ExpectedObserved Intermediate Structure Method Mass Mass 10B

2.95 LCMS Method 4 473.3 [M + H]⁺ 473.8 [M + H]⁺ 10C

2.86 LCMS Method 4 459.3 [M + H]⁺ 459.5 [M + H]⁺ 10D

1.21 LCMS Method 2 441.3 [M + H]⁺ 441.7 [M + H]⁺

Intermediate 11A: 4-(2-chlorophenyl)tetrahydro-2H-pyran-4-ol

To a solution of 1-bromo-2-chlorobenzene (3 g, 15.67 mmol) in THE (25mL) at 25° C. was added iso-propyl magnesium chloride (7.8 mL, 15.67mmol, 2.0 M in THF), and the reaction mixture was stirred at 25° C. for2 hr. Then, a solution of tetrahydro-4H-pyran-4-one (1.57 g, 15.67 mmol)in THE (5 mL) was added dropwise. After the addition, the mixture wasstirred at 25° C. for another 16 hr. The reaction mixture was thenquenched with a saturated solution of NH₄C₁ (30 mL), extracted withEtOAc (3×20 mL) and the combined organic phases were dried with Na₂SO₄,filtered and concentrated. The crude product was purified by FCC (0-50%EtOAc/petroleum ether) to afford the title intermediate (900 mg, 4.23mmol, 27.00% yield) as a yellow oil.

LCMS: Rt: 1.52 min (LCMS Method 5) MS m/z 195.1 [M−H₂O+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 7.56-7.53 (m, 1H), 7.44-7.38 (m, 1H),7.34-7.19 (m, 2H), 4.07-3.95 (m, 2H), 3.94-3.85 (m, 2H), 3.22-2.96 (m,1H), 2.48-2.36 (m, 2H), 2.02-1.90 (m, 2H).

The following compound in Table 11 was prepared using a similarprocedure using the relevant starting materials:

TABLE 11 Intermediate 11B Inter- Rt(min) Expected Observed mediateStructure Method Mass Mass 11B

0.73 LCMS Method 5 213.0 [M − OH]⁺ 213.1 [M − OH]⁺

Intermediate 12A: 4-(2-bromo-4-fluorophenyl)-3,6-dihydro-2H-pyran

To a solution of 2-bromo-4-fluoro-1-iodobenzene (2.0 g, 6.65 mmol) in amixture of dioxane (20 mL) and H₂O (2 mL) was added2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(1.40 g, 6.65 mmol), K₂CO₃ (2.76 g, 19.94 mmol) and Pd(dppf)Cl₂ (486 mg,0.66 mmol). The reaction mixture was stirred at 60° C. for 4 hr under N₂and then warmed to 80° C. for another 1 hr. The reaction mixture wasquenched with saturated solution of NaCl (20 mL) and this solution wasextracted with EtOAc (3×20 mL). The combined organic phases were driedover Na₂SO₄, filtered and concentrated. The crude product was purifiedby FCC (0-30% EtOAc/petroleum ether) to afford the title intermediate(1.2 g, 4.67 mmol, 70.22% yield) as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 7.32-7.30 (m, 1H), 7.15-7.13 (m, 1H),7.00-6.98 (m, 1H), 5.70-5.68 (m, 1H), 4.31-4.29 (m, 2H), 3.94-3.91 (m,2H), 2.42-2.39 (m, 2H).

Intermediate 12B: tert-butyl4-(2-(3,6-dihydro-2H-pyran-4-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

To a solution of tert-butyl4-(2-bromophenyl)-3,6-dihydropyridine-1(2H)-carboxylate3 (Intermediate13J, 500 mg, 1.48 mmol) in dioxane (5 mL) and H₂O (0.5 mL) was added2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(311 mg, 1.48 mmol), K₂CO₃ (614 mg, 4.44 mmol) and Pd(dppf)Cl₂ (110 mg,0.15 mmol). The reaction mixture was stirred for 16 hr at 80° C. underN₂. The reaction mixture was then quenched with H₂O (10 mL), extractedwith EtOAc (3×5 mL), washed with brine (10 mL), dried with Na₂SO₄,filtered and concentrated. The crude product was purified by FCC (5-10%EtOAc/petroleum ether) to give the title compound (350 mg, 1.02 mmol) asa colorless oil.

LCMS: Rt: 1.12 min (LCMS Method 6) MS m/z 242.3 [M-Boc+H]⁺.

Intermediate 13A: tert-butyl4-(2-(benzyloxy)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

To a mixture of 1-(benzyloxy)-2-bromobenzene (6.53 mL, 34.3 mmol),tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(10.1 g, 32.7 mmol), PdCl₂(dppf)·CH₂Cl₂ (1.334 g, 1.633 mmol) andpotassium phosphate (20.80 g, 98 mmol) was added dioxane (115 mL) andwater (15 mL). The reaction was then stirred at 100° C. for 16 hours.LCMS showed clean reaction. The reaction was washed with water, driedover magnesium sulfate, filtered and concentrated. The residue was thenpurified by FCC (0-20% EtOAc/heptanes) to yield the title compound(11.86 g, 32.1 mmol) as a beige oil.

LCMS: Rt: 1.37 min (LCMS Method 2) MS m/z 265.9 [M-Boc+H]⁺.

Intermediate 13B: tert-butyl4-(2-(trifluoromethoxy)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

1-bromo-2-(trifluoromethoxy)benzene (10 g, 41.5 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(14.11 g, 45.6 mmol), PdCl₂(dppf)·CH₂Cl₂ adduct (1.694 g, 2.075 mmol),and K₃PO₄ (26.4 g, 124 mmol) were added to a 500 mL three neck flask.The reactants were dissolved in degassed dioxane (160 mL) and degassedwater (40 mL) and stirred at 100° C. for 5 hours. The reaction was thencooled to RT and filtered through a pad of celite, washing with EtOAc(100 mL). The filtrate was diluted with 500 mL of EtOAc and washed withwater (3×25 mL) and brine (1×10 mL), dried over MgSO₄, filtered andconcentrated. The residue was then dissolved in 100 mL of EtOAc andfiltered through a second pad of celite and concentrated and thenpurified by FCC (0 →2500 EtOAc/heptanes) to yield the title intermediateas a yellow liquid (14.09 g, 41 mmol).

Rt: 3.13 min (LCMS Method 3). MS m/z 288.1 [M-Boc+formate]⁺.

¹H NMR (400 MHz, CDCl₃) δ 7.35-7.21 (m, 4H), 5.83-5.76 (m, 1H), 4.08 (q,J=2.8 Hz, 2H), 3.63 (t, J=5.6 Hz, 2H), 2.47 (dq, J=5.4, 3.0 Hz, 2H),1.52 (s, 9H).

The following compounds in Table 12 were prepared using a similarprocedure and the relevant starting materials:

TABLE 12 Intermediates 13C to 13I Retention time (min) and ExpectedObserved Intermediate Structure Method Mass Mass 13C

1.20 LCMS Method 2 226.1 [M − Boc + H]⁺ 226.3 [M − Boc + H]⁺ 13D

2.36 LCMS Method 3 176.1 [M − Boc + H]⁺ 176.1 [M − Boc + H]⁺ 13E

1.21 LCMS Method 2 190.1 [M − Boc + H]⁺ 190.3 [M − Boc + H]⁺ 13F

1.31 LCMS Method 1 224.1 [M − Boc + H]⁺ 223.9 [M − Boc + H]⁺ 13G

0.88 LCMS Method 5 360.2 [M + H]⁺ Not found 13H

0.891 LCMS Method 5 378.2 [M + H]⁺ Not found 13I

0.977 LCMS Method 5 260.1 [M − Boc + H]⁺ 260.0 [M − Boc + H]⁺

Intermediate 13J: tert-butyl4-(2-bromophenyl)-3,6-dihydropyridine-1(2H)-carboxylate

To a solution of 1-bromo-2-iodobenzene (1 g, 3.53 mmol) in dioxane (10mL) and H₂O (1 mL) was added tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate(984 mg, 3.18 mmol), K₂CO₃ (1.46 g, 10.59 mmol) and Pd(dppf)Cl₂ (256 mg,0.35 mmol). The reaction mixture was stirred for 2 hr at 60° C. under N₂and the reaction mixture was then quenched with H₂O (20 mL), extractedwith EtOAc (3×10 mL), washed with NaCl (20 mL), dried with Na₂SO₄,filtered and concentrated. The crude product was purified by FCC (0-2.5%EtOAc/PE) to give and then purified a second time using the sameconditions to yield the title compound (500 mg, 1.48 mmol).

¹H NMR (400 MHz, CD₃OD) δ 7.56 (d, J=8.0 Hz, 1H), 7.34-7.28 (m, 1H),7.22-7.14 (m, 2H), 5.63 (br s, 1H), 4.03 (br s, 2H), 3.64 (t, J=5.0 Hz,2H), 2.42 (d, J=1.5 Hz, 2H), 1.50 (s, 9H).

Intermediate 13K: tert-butyl4-(2-(benzyloxy)-5-fluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate

To a solution of 1-(benzyloxy)-2-bromo-4-fluorobenzene (2.0 g, 7.11mmol) in a mixture of dioxane (20 mL) and H₂O (2 mL) was addedtert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate(2.20 g, 7.11 mmol), K₂CO₃ (2.95 g, 21.34 mmol) and Pd(dppf)Cl₂ (520 mg,0.71 mmol). The reaction mixture was stirred at 80° C. for 4 hr under N₂and the reaction mixture was then quenched with a saturated solution ofNH₄C₁ (20 mL). This solution was then extracted with EtOAc (3×20 mL) andthe combined organic phases were dried over Na₂SO₄, filtered andconcentrated. The crude product was purified FCC (0-30% EtOAc/petroleumether) to give the title intermediate (1.87 g, 4.88 mmol) as a yellowoil.

¹H NMR (400 MHz, CDCl₃) δ 7.43-7.36 (m, 4H), 7.36-7.30 (m, 1H),6.91-6.85 (m, 3H), 5.80 (br s, 1H), 5.03 (s, 2H), 4.04 (br s, 2H),3.57-3.54 (m, 2H), 2.50 (br s, 2H), 1.49 (s, 9H).

Intermediate 14A: tert-butyl4-(2-(trifluoromethoxy)phenyl)piperidine-1-carboxylate

tert-butyl4-(2-(trifluoromethoxy)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate(Intermediate 13B, 14.09 g, 41.0 mmol) was added to a 250 mL rb flaskfollowed by 10% Pd—C(4 grams). EtOH (82 mL) was added to the flask andthe reaction was stirred under an atmosphere of hydrogen for 2 hours.Next, hydrogen was bubbled through the reaction for 4 hours. Thereaction was filtered through a pad of celite twice and the filtrate wasconcentrated to yield the title intermediate as a clear, colorless oil(13.75 g, 39.8 mmol).

Rt: 3.18 min (LCMS Method 3). MS m/z 290.3 [M-Boc+formate]⁺.

¹H NMR (400 MHz, CDCl₃) δ 7.36-7.19 (m, 4H), 4.36-4.20 (m, 2H), 3.09(tt, J=12.1, 3.5 Hz, 1H), 2.85 (td, J=13.2, 2.5 Hz, 2H), 1.78 (d, J=13.1Hz, 2H), 1.64 (td, J=12.5, 4.0 Hz, 2H), 1.51 (s, 9H).

The following compounds in Table 14 were prepared using a similarprocedure and the relevant starting materials:

TABLE 14 Intermediates 14B to 14I Retention time (min) and ExpectedObserved Intermediate Structure Method Mass Mass 14B

3.09 LCMS Method 3 226.1 [M − Boc + H]⁺ 226.2 [M − Boc + H]⁺ 14C

1.24 LCMS Method 1 192.1 [M − Boc + H]⁺ 192.3 [M − Boc + H]⁺ 14D

0.951 LCMS Method 6 272.1 [M − Boc + formate]⁺ 272.0 [M − Boc +formate]⁺ 14E

1.04 LCMS Method 2 178.1 [M − Boc + H]⁺ 177.9 [M − Boc + H]⁺ 14F

0.868 LCMS Method 5 244.2 [M − Boc − OH]⁺ 244.1 [M − Boc − OH]⁺ 14G

1.036 LCMS Method 6 262.2 [M − Boc − OH]⁺ 262.2 [M − Boc − OH]⁺ 14H

1.06 LCMS Method 6 264.2 [M − Boc + H]⁺ 264.4 [M − Boc + H]⁺ 14I

1.05 LCMS Method 6 240.1 [M − Boc + formate]⁺ 240.3 [M − Boc + formate]⁺

Intermediate 14J: tert-butyl4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidine-1-carboxylate

To a solution of tert-butyl4-(2-(3,6-dihydro-2H-pyran-4-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate(Intermediate 12B, 350 mg, 1.02 mmol) in MeOH (5 mL) was added Pd(OH)₂/C(100 mg, 20%) and the reaction mixture was stirred for 3 hr at 25° C.under a balloon of H₂. The reaction mixture was filtered andconcentrated to give the title compound (286 mg, 0.83 mmol) as a lightyellow oil that was used without further purification.

Rt: 1.11 min (LCMS Method 6). MS m/z 246.4 [M-Boc+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.28-7.25 (m, 1H), 7.23-7.19 (m, 1H),7.19-7.14 (m, 2H), 4.22 (d, J=13.2 Hz, 2H), 4.05 (dd, J=4.1, 11.3 Hz,2H), 3.62 (m, 2H), 3.21-3.02 (m, 2H), 2.92 (br s, 2H), 1.91-1.78 (m,2H), 1.75-1.60 (m, 6H), 1.52-1.48 (m, 9H),

Intermediate 15A: tert-butyl4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidine-1-carboxylate

To a solution of tert-butyl4-(5-fluoro-2-hydroxyphenyl)piperidine-1-carboxylate (Intermediate 14J,850 mg, 2.88 mmol) in THF (10 mL) at 0° C. was addedtetrahydro-2H-pyran-4-ol (669 mg, 5.76 mmol) and PPh₃ (1.51 g, 5.76mmol) and then DIAD (1.16 g, 5.76 mmol) was added dropwise. The reactionwas stirred at 25° C. for 16 hr under N₂. The reaction mixture wasquenched with H₂O (20 mL), extracted with EtOAc (3×10 mL), dried withNa₂SO₄, filtered and the filtrate was concentrated. The crude productwas purified by FCC (0-80% EtOAc/PE) to yield the title compound (850mg, 2.23 mmol) as yellow solid.

Rt: 1.126 min (LCMS Method 6) MS m/z 280.3 [M-Boc+H]⁺.

The following compound in Table 15 was prepared using a similarprocedure and the relevant starting materials:

TABLE 15 Intermediate 15B Retention time (min) and Expected ObservedIntermediate Structure Method Mass Mass 15B

1.133 LCMS Method 6 262.2 [M − Boc + H]⁺ 262.2 [M − Boc + H]⁺

Intermediate 16A: 4-(2-(trifluoromethoxy)phenyl)piperidine

tert-butyl 4-(2-(trifluoromethoxy)phenyl)piperidine-1-carboxylate(Intermediate 14A, 13.75 g, 39.8 mmol) was added to a 500 mL RB flaskand dissolved in DCM (80 mL). The reaction was cooled to 0° C. andincubated for 10 minutes and then TFA (80 mL, 39.8 mmol) was added andthe reaction was slowly warmed to RT and stirred for 3 hours. Thereaction was then cooled to 0° C. and quenched with 6N KOH (300 mL). DCM(200 mL) was added and the layers were separated and the aqueous phasewas extracted with DCM (5×100 mL). The combined organic layers werewashed brine (1×50 mL), dried over MgSO₄, filtered and concentrated toyield the title intermediate (9090 mg, 37.1 mmol) as a tan liquid thatwas used without further purification.

LCMS: Rt: 0.67 min (LCMS Method 3), MS m/z 246.1 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 7.37 (d, J=7.5 Hz, 1H), 7.34-7.20 (m, 3H),3.29-3.18 (m, 2H), 3.08 (tt, J=12.0, 3.7 Hz, 1H), 2.82 (m, 2H), 2.71 (s,1H), 1.82 (s, 2H), 1.68 (m, 2H).

The following compounds in Table 16 were prepared using a similarprocedure and the relevant starting materials:

TABLE 16 Intermediates 16B to 16M Retention time (min) and ExpectedObserved Intermediate Structure Method Mass Mass 16B

1.10 LCMS Method 3 226.1 [M + H]⁺ 226.0 [M + H]⁺ 16C

0.50 LCMS Method 1 192.1 [M + H]⁺ 192.2 [M + H]⁺ 16D

0.92 LCMS Method 6 228.3 [M + H]⁺ 228.1 [M + H]⁺ 16E

0.62 LCMS Method 2 178.1 [M + H]⁺ 178.3 [M + H]⁺ 16F

1.20 LCMS Method 6 280.2 [M + H]⁺ 280.2 [M + H]⁺ 16G

0.86 LCMS Method 6 262.2 [M + H]⁺ 262.2 [M + H]⁺ 16H

0.86 LCMS Method 5 262.2 [M + H]⁺ 262.1 [M + H]⁺ 16I

0.69 LCMS Method 5 280.2 [M + H]⁺ 280.1 [M + H]⁺ 16J

0.884 LCMS Method 5 264.2 [M + H]⁺ 264.2 [M + H]⁺ 16K

0.968 LCMS Method 5 284.1 [M + H]⁺ 284.1 [M + H]⁺ 16L

0.884 LCMS Method 5 246.2 [M + H]⁺ 246.4 [M + H]⁺ 16M

0.377 LCMS Method 5 196.1 [M + H]⁺ 196.2 [M + H]⁺

Intermediate 16N: 4-(2-(tetrahydro-2H₁-pyran-4-yl)phenyl)piperidinehydrochloride

tert-butyl4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidine-1l-carboxylate(Intermediate 14J, 0.3 g, 0.868 mmol) was added to HCl/dioxane (4M, 3mL) at 25° C. The resulting solution was stirred at 25° C. for 1 hr. Thereaction mixture was concentrated to afford the title intermediate (150mg, 0.532 mmol) that was used without further purification.

LCMS: Rt: 0.67 min (LCMS Method 6), MS m/z 246.2 [M+H]⁺.

Intermediate 17A: tert-butyl6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[13.4]octane-2-carboxylate

4-(2-(trifluoromethoxy)phenyl)piperidine (Intermediate 16A, 9090 mg,37.1 mmol), tert-butyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate (8350mg, 37.1 mmol) and 4 angstrom molecular sieves (10 grams) were added toa 500 mL rb flask followed by DCM (180 mL). The reaction was stirred for90 minutes and then sodium triacetoxyborohydride (15.7 g, 74.1 mmol) wasadded in 3 portions over 5 minutes. The reaction was then stirred for 16hours. The reaction was then warmed to 35° C. for 3 hours and then itwas quenched with 1N KOH (200 mL) and transferred to a 500 mL separationfunnel. The aqueous phase was extracted with DCM (5×100 mL) and thecombined organic layers were washed with brine (1×50 mL), dried overMgSO₄ and purified by FCC (0-7% MeOH (1% NH₄OH)/DCM) to yield the titleintermediate (9090 mg, 20.0 mmol) as a tan liquid.

LCMS: Rt: 3.30 mi (LCMS Method 4), MS m/z 455.3 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 7.38 (d, J=7.3 Hz, 1H), 7.31-7.20 (m, 3H),3.92-3.83 (m, 2H), 3.83-3.71 (m, 3H), 3.13 (s, 2H), 3.04-2.89 (m, 1H),2.63 (s, 1H), 2.24-2.01 (m, 3H), 1.90 (m, 7H), 1.62 (s, 1H), 1.47 (d, J2.9 Hz, 9H).

The following compounds in Table 17 were prepared using a similarprocedure and the relevant starting materials:

TABLE 17 Intermediates 17B to 17E Retention time (min) and ExpectedObserved Intermediate Structure Method Mass Mass 17B

1.62 LCMS Method 3 435.2 [M + H]⁺ 434.9 [M + H]⁺ 17C

0.82 LCMS Method 1 401.3 [M + H]⁺ 401.5 [M + H]⁺ 17D

3.03 LCMS Method 3 437.3 [M + H]⁺ 437.4 [M + H]⁺ 17E

1.116 LCMS Method 5 473.3 [M + H]⁺ 473.5 [M + H]⁺

Intermediate 17F:(R)-(1-fluorocyclopropyl)(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanoneor(S)-(1-fluorocyclopropyl)(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanoneand Intermediate 17G:(R)-(1-fluorocyclopropyl)(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanoneor(S)-(1-fluorocyclopropyl)(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanoneand Example 1711:rac-(1-fluorocyclopropyl)(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone

To a MeOH (30 mL) solution of 2-(piperidin-4-yl)phenol (Intermediate16E, 1722 mg, 4.25 mmol) and2-(1-fluorocyclopropanecarbonyl)-2-azaspiro[3.4]octan-6-one(Intermediate 2C, 748 mg, 3.54 mmol), was added TEA (1.974 mL, 14.16mmol) and zinc chloride (0.5M in THF, 10.62 mL, 5.31 mmol). The solutionwas stirred at 50° C. for 2 hr and then it was cooled to 0° C. andsodium cyanoborohydride (445 mg, 7.08 mmol) was added and then thereaction was warmed to RT and stirred for 2 hr. The solvent was removedunder reduced pressure and the residue was dissolved in DCM, washed withwater and dried over sodium sulfate and concentrated. The residue wasthen purified by FCC (0-5% MeOH/DCM) to yield Example 17H and then theenantiomers were separated by chiral SFC (CHIRALCEL© OD-H 20×250 mm, 30%EtOH (0.1% DEA)/CO₂, 100 bar, 60 mL/min). The faster running enantiomerwas isolated as Intermediate 17F (426 mg, 1.09 mmol) and the slowerrunning enantiomer was isolated as Intermediate 17G (463 mg, 1.18 mmol).

Intermediate 17F

SFC: Rt: 3.05 min (Chiralpak® IB 4.6×100 mm, 5 μM, 5-55% MeOH (10 mMNH₄OH)/CO2, 5 mL/min).

LCMS: Rt: 1.99 min (LCMS Method 4), MS m/z 373.3 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.10 (d, J=7.5 Hz, 1H), 7.03-6.93 (m, 1H),6.83-6.70 (m, 2H), 4.48-4.22 (m, 2H), 4.05-3.84 (m, 2H), 3.14 (d, J=11.5Hz, 2H), 2.94 (m, 1H), 2.76-2.60 (m, 1H), 2.33-2.08 (m, 3H), 2.05-1.89(m, 3H), 1.87-1.69 (m, 5H), 1.65-1.51 (m, 1H), 1.30-1.21 (m, 4H).

Intermediate 17G

SFC: Rt: 3.25 min (Chiralpak® IB 4.6×100 mm, 5 μM, 5-55% MeOH (10 mMNH₄OH)/CO2, 5 mL/min).

LCMS: Rt: 1.98 min (LCMS Method 4), MS m/z 373.0 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.10 (dd, J=7.7, 1.4 Hz, 1H), 6.98 (td, J=7.7,1.6 Hz, 1H), 6.82-6.69 (m, 2H), 4.47-4.24 (m, 2H), 4.04-3.81 (m, 2H),3.21-3.10 (m, 2H), 2.94 (m, 1H), 2.69 (q, J=7.8 Hz, 1H), 2.25 (m, 1H),2.20-2.08 (m, 2H), 1.96 (m, 3H), 1.86-1.70 (m, 5H), 1.59 (m, 1H),1.31-1.21 (m, 4H).

Intermediate 17H

LCMS: Rt: 0.91 min (LCMS Method 2), MS m/z 372.9 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.10 (dd, J=7.4, 1.7 Hz, 1H), 6.99 (td, J=7.6,1.7 Hz, 1H), 6.89-6.66 (m, 2H), 4.48-4.23 (m, 2H), 4.10-3.80 (m, 2H),3.22 (d, J=11.8 Hz, 2H), 2.97 (d, J=14.5 Hz, 2H), 2.82 (s, 1H), 2.28 (s,3H), 2.10-1.71 (m, 8H), 1.62 (d, J=8.3 Hz, 1H), 1.36-1.16 (m, 3H).

The following compounds in Table 18 were prepared using a similarprocedure and the relevant starting materials:

TABLE 18 Intermediates 17I to 17K Retention time (min) and ExpectedObserved Intermediate Structure Method Mass Mass 17I

0.916 LCMS Method 6 391.2 [M + H]⁺ 391.4 [M + H]⁺ 17J

1.62 LCMS Method 6 493.3 [M + H]⁺ 493.5 [M + H]⁺ 17K

1.28 LCMS Method 2 455.3 [M + H]⁺ 455.5 [M + H]⁺

Intermediate 18A:6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane

tert-butyl6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate(Intermediate 17A, 9090 mg, 20.00 mmol) was added to a 500 mL rb flaskfollowed by DCM (100 mL). The reaction was stirred at 0° C. for 10minutes and then TFA (50 mL) was slowly added. The reaction was warmedto RT and stirred for 1 hour and then the reaction was concentrated. Theresidue was taken up in DCM (200 mL) and quenched with 1N KOH (100 mL).The solution was transferred to a 500 mL separatory funnel and thelayers were separated. The aqueous phase was extracted with 20% MeOH/DCM(5×100 mL) and the combined organic layers were washed with brine (1×50mL), dried over MgSO₄, filtered and concentrated. The resulting brownoil (7690 mg, 21.7 mmol) was used in the next step without furtherpurification.

LCMS: Rt: 0.65 min (LCMS Method 3) MS m/z 355.2 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.42-7.40 (m, 1H), 7.35-7.23 (m, 3H),3.73-3.56 (m, 3H), 3.17-3.15 (m, 2H), 2.99-2.90 (m, 1H), 2.69-2.58 (m,1H), 2.26 (dd, J=12.9, 7.3 Hz, 1H), 2.22-2.06 (m, 2H), 2.06-1.82 (m,3H), 1.82-1.69 (m, 5H), 1.58-1.50 (m, 1H).

The following compounds in Table 19 were prepared using a similarprocedure using the relevant starting materials:

TABLE 19 Intermediates 18B to 18H Rt(min) Expected Observed IntermediateStructure Method Mass Mass 18B

0.57 LCMS Method 1 335.2 [M + H]⁺ 335.0 [M + H]⁺ 18C

0.43 LCMS Method 1 301.2 [M + H]⁺ 301.4 [M + H]⁺ 18D

0.85 LCMS Method 2 337.2 [M + H]⁺ 337.3 [M + H]⁺ 18E

0.765 LCMS Method 5 373.3 [M + H]⁺ 373.2 [M + H]⁺ 18F

0.58 LCMS Method 5 401.3 [M + H]⁺ 401.2 [M + H]⁺ 18G

0.801 LCMS Method 5 389.3 [M + H]⁺ 389.3 [M + H]⁺ 18H

0.51 LCMS Method 1 355.3 [M + H]⁺ 355.4 [M + H]⁺

Intermediate 19A:(R)-(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone

To a solution of DMF (5 mL) and DCM (5 mL) oxetane-3-carboxylic acid(0.633 g, 6.20 mmol) was added followed by TBTU (1.991 g, 6.20 mmol).The reaction was stirred for 10 min and then(R)-2-(1-(2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenol (Intermediate4S, 0.888 g, 3.1 mmol) and DIEA (2.166 mL, 12.40 mmol) were added as asolution in DMF (3 mL) and DCM (5 mL). The resulting mixture was thenstirred at RT for 16 hours. The reaction mixture was concentrated underreduced pressure and the residue was dissolved in a mixture of THE (17mL) and water (3 mL) and lithium hydroxide (742 mg, 31.0 mmol) wasadded. MeOH (1 mL) was added and the reaction was stirred at 60° C. for3 hours. The reaction was concentrated and the residue was purified byFCC (0-8% MeOH (1% 7N NH₃ in MeOH)/DCM) to yield the title compound as acream colored solid (790 mg, 2.11 mmol).

LCMS: Rt: 1.52 min (LCMS Method 3) MS m/z 371.4 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.12 (dd, J=7.6, 1.6 Hz, 1H), 7.07-6.95 (m,1H), 6.78 (dd, J=17.5, 8.0 Hz, 2H), 4.80 (m, 4H), 4.08-3.80 (m, 5H),3.17 (m, 2H), 2.97 (m, 1H), 2.72 (m, 1H), 2.31-2.11 (m, 3H), 1.99 (m,2H), 1.93-1.72 (m, 6H), 1.70-1.53 (m, 1H).

Example 1A(R)-2-(6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole

(R)-2-(1-(2-(1,3,4-oxadiazol-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenol(Intermediate 6A, 36 mg, 0.10 mmol), 2-oxaspiro[3.3]heptan-6-yl4-methylbenzenesulfonate (Intermediate 7A, 30 mg, 0.11 mmol), and cesiumcarbonate (66 mg, 0.20 mmol) were suspended in DMF (0.5 mL). Thereaction was heated at 80° C. for 2 days, diluted with ethyl acetate (50mL), washed with water (2×10 mL), and concentrated. The residue waspurified by preparative HPLC (XBridge 30×50 mm 35-60% MeCN/H₂O (5 mMNH₄OH)), and by FCC (0-5% MeOH(10% 7N NH₃)/DCM) to yield the titlecompound (25 mg, 0.055 mmol) as a white foamy solid. LCMS: Rt: 2.15 min(LCMS Method 4) MS m/z 451.5 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 7.19 (d, J=7.5 Hz, 1H),7.16-7.08 (m, 1H), 6.91 (t, J=7.5 Hz, 1H), 6.74 (d, J=8.1 Hz, 1H), 4.78(s, 2H), 4.71 (s, 2H), 4.59 (m, 1H), 4.17-3.99 (m, 4H), 3.17 (m, 2H),3.03-2.91 (m, 1H), 2.90-2.80 (m, 2H), 2.79-2.66 (m, 1H), 2.38-2.27 (m,3H), 2.23-1.92 (m, 5H), 1.89-1.69 (m, 5H), 1.68-1.55 (m, 1H).

Example 1B:(R)-2-(6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole

(R)-2-(1-(2-(1,3,4-oxadiazol-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)-4-fluorophenol(Intermediate 6B, 22 mg, 0.059 mmol), 2-oxaspiro[3.3]heptan-6-yl4-methylbenzenesulfonate (Intermediate 7A, 17 mg, 0.065 mmol), andcesium carbonate (38 mg, 0.12 mmol) were suspended in DMF (0.5 mL). Thereaction was heated at 80° C. for 16 hr, diluted with ethyl acetate,washed with water, and concentrated. The residue was purified bypreparative HPLC (XBridge 30×50 mm 35-60% MeCN/H₂O (5 mM NH₄OH)), and byFCC (0-40% ethyl acetate (10% 7N NH₃)/heptane) to yield the titlecompound (7.3 mg, 0.015 mmol) as a white solid.

LCMS: Rt: 2.27 min (LCMS Method 4) MS m/z 469.4 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.36 (s, 1H), 6.90 (dd, J=9.8, 3.0 Hz, 1H),6.82 (td, J=8.4, 3.1 Hz, 1H), 6.70 (dd, J=8.9, 4.5 Hz, 1H), 4.72 (d,J=5.0 Hz, 2H), 4.67 (s, 2H), 4.53 (p, J=6.7 Hz, 1H), 4.17-3.95 (m, 4H),3.16-3.13 (m, 2H), 2.93 (tt, J=12.0, 4.0 Hz, 1H), 2.86-2.76 (m, 2H),2.70 (tt, J=9.3, 7.2 Hz, 1H), 2.33-2.25 (m, 3H), 2.19-1.90 (m, 5H),1.86-1.75 (m, 3H), 1.75-1.54 (m, 3H).

Example 1C:2-((R)-6-(4-(2-(((R)-1,4-dioxan-2-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole

(R)-ethyl5-(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole-2-carboxylate(Intermediate 6E, 180 mg, 0.422 mol), (R)-(1,4-dioxan-2-yl)methyl4-methylbenzenesulfonate (Intermediate 7B, 138 mg, 0.506 mmol), andcesium carbonate (413 mg, 1.27 mmol) were suspended in DMF (1.8 mL), andthe reaction was stirred at RT for 16 hours. Additional cesium carbonate(275 mg, 0.844 mmol) was added, and the reaction was stirred for anadditional 16 hours at RT. Next, a solution of 4N HCl was added toadjust pH to 2, and the reaction was stirred at RT for 16 hours. Theresidue was concentrated, and purified by C₁₈ reverse phase FCC (0-80%MeCN/H₂O (5 mM NH₄OH)) to afford the title compound (93 mg, 0.20 mmol).

LCMS: Rt: 2.10 min (LCMS Method 4) MS m/z 455.3 [M+H]⁺.

¹H NMR (DMSO-d₆) δ 8.69-8.55 (m, 1H), 7.15 (d, J=6.8 Hz, 2H), 7.00-6.83(m, 2H), 4.06-3.82 (m, 8H), 3.81-3.73 (m, 1H), 3.72-3.58 (m, 2H),3.55-3.42 (m, 2H), 3.30-3.26 (m, 1H), 3.16-2.94 (m, 2H), 2.92-2.73 (m,1H), 2.63-2.56 (m, 1H), 2.26-2.09 (m, 1H), 2.07-1.42 (m, 10H).

Example 1D:(R)-2-(6-(4-(2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole

(R)-ethyl5-(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole-2-carboxylate(Intermediate 6E, 75 mg, 0.18 mmol), oxetan-3-yl4-methylbenzenesulfonate (80 mg, 0.35 mmol), and cesium carbonate (172mg, 0.528 mmol) were suspended in DMF (0.70 mL), and the reaction wasstirred at 80° C. for 16 hours. Next, a solution of 4N HCl was added toadjust pH to 2, and the reaction was stirred at RT for 5 hours. A 2Msolution of LiOH was added to adjust pH to 8, and the solution wasextracted with DCM. The combined organic layers were concentrated andthe residue was purified by preparative HPLC (XBridge 30×50 mm 25-50%MeCN/H₂O (5 mM NH₄OH)) to afford the title compound (28 mg, 0.065 mmol).

LCMS: Rt: 1.99 min (LCMS Method 4) MS m/z 411.2 [M+H]⁺.

¹H NMR (DMSO-d₆) δ 8.63 (s, 1H), 7.28-7.05 (m, 2H), 6.94 (br s, 1H),6.53 (d, J=12.2 Hz, 1H), 5.28 (br s, 1H), 5.01-4.88 (m, 2H), 4.54 (br s,2H), 4.13-3.85 (m, 4H), 3.70-3.47 (m, 1H), 3.29 (s, 1H), 3.15-2.84 (m,2H), 2.23-1.38 (m, 12H).

Example 1E:2-((R)-6-(4-(2-(((S)-1,4-dioxan-2-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole

(R)-ethyl5-(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole-2-carboxylate(Intermediate 6E, 150 mg, 0.352 mmol), (S)-(1,4-dioxan-2-yl)methyl4-methylbenzenesulfonate (Intermediate 7D, 115 mg, 0.422 mmol), andcesium carbonate (344 mg, 1.06 mmol) were suspended in DMF (1.5 mL), andthe reaction was stirred at RT for 16 h. Additional cesium carbonate(229 mg, 0.703 mmol) was added, and the reaction was stirred for another16 hours at RT. A solution of 4N HCl was then added to adjust the pH to2, and the reaction was stirred at RT for 16 hours. A 2M solution ofLiOH was then added to adjust the pH to 8, and the solution wasextracted with DCM. The combined organic layers were concentrated andthe residue was purified by HPLC (XBridge 30×50 mm 25-50% MeCN/H₂O (5 mMNH₄OH)), and further by FCC (0-10% MeOH/DCM) to afford the titlecompound (73 mg, 0.16 mmol).

LCMS: Rt: 2.09 min (LCMS Method 4) MS m/z 455.3 [M+H]⁺.

¹H NMR (DMSO-d₆) δ 8.62 (s, 1H), 7.18-7.09 (m, 2H), 6.95-6.86 (m, 2H),4.04-3.82 (m, 8H), 3.81-3.74 (m, 1H), 3.72-3.59 (m, 2H), 3.54-3.44 (m,2H), 3.07-2.96 (m, 2H), 2.87-2.75 (m, 1H), 2.64-2.54 (m, 1H), 2.19-2.09(m, 1H), 2.04-1.77 (m, 5H), 1.77-1.65 (m, 3H), 1.65-1.40 (m, 3H).

Example 1F: (R)-ethyl5-(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole-2-carboxylate

(R)-ethyl5-(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole-2-carboxylate(Intermediate 6E, 103 mg, 0.241 mmol), 3-hydroxy-3-methylbutyl4-methylbenzenesulfonate (Intermediate 7G, 69 mg, 0.27 mmol), and cesiumcarbonate (236 mg, 0.724 mmol) were suspended in DMF (1.0 mL), and thereaction was stirred at RT for 16 hours. Next, a solution of 4N HCl wasadded to adjust the pH to 2, and the reaction was stirred at RT for 16hours. A 2M solution of LiOH was then added to adjust the pH to 8, andthe solution was extracted with DCM. The combined organic layers wereconcentrated and the residue was purified by preparative HPLC (XBridge30×50 mm 25-50% MeCN/H₂O (5 mM NH₄OH)), and further by FCC (0-10%MeOH/DCM) to afford the title compound (36 mg, 0.080 mmol).

LCMS: Rt: 2.13 min (LCMS Method 4) MS m/z 441.2 [M+H]⁺.

¹H NMR (DMSO-d₆) δ 8.62 (s, 1H), 7.19-7.09 (m, 2H), 6.94 (d, J=8.3 Hz,1H), 6.87 (t, J=7.3 Hz, 1H), 4.36 (s, 1H), 4.06 (t, J=6.8 Hz, 2H),4.02-3.87 (m, 4H), 3.00 (br s, 2H), 2.86 (br s, 1H), 2.63-2.54 (m, 1H),2.22-2.10 (m, 1H), 2.04-1.77 (m, 7H), 1.76-1.63 (m, 3H), 1.63-1.51 (m,2H), 1.50-1.39 (m, 1H), 1.20-1.14 (m, 6H).

Example 1G:(R)-2-(6-(4-(2-(oxetan-3-ylmethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole

(R)-2-(1-(2-(1,3,4-thiadiazol-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenol(Intermediate 5D, 7.6 mg, 0.021 mmol) was dissolved in DMF (0.3 mL) and3-(iodomethyl)oxetane (8.1 mg, 0.041 mmol) was added followed by cesiumcarbonate (13 mg, 0.041 mmol). The reaction was stirred at RT for 16hours and then filtered and purified by preparative HPLC (XBridge 30×50mm 35-60% MeCN/H₂O (5 mM NH₄OH)) to afford the title compound (3.3 mg,0.0073 mmol).

LCMS: Rt: 2.11 min (LCMS Method 4) MS m/z 441.4 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.63 (s, 1H), 7.22-7.11 (m, 2H), 6.99-6.88 (m,2H), 4.88 (dd, J=8.0, 6.1 Hz, 2H), 4.66 (t, J=6.0 Hz, 2H), 4.18 (d,J=5.8 Hz, 2H), 4.11-3.95 (m, 4H), 3.48 (m, 1H), 3.14 (s, 2H), 3.03 (m,1H), 2.78-2.62 (m, 1H), 2.30 (dd, J=12.9, 7.3 Hz, 1H), 2.14 (q, J=11.0,9.9 Hz, 2H), 2.08-1.91 (m, 3H), 1.89-1.65 (m, 5H), 1.65-1.54 (m, 1H).

Example 1H:(R)-2-(6-(4-(2-((3-fluorooxetan-3-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole

(R)-2-(1-(2-(1,3,4-thiadiazol-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenol(Intermediate 5D, 9.4 mg, 0.025 mmol) was dissolved in DMF (0.3 mL) and(3-fluorooxetan-3-yl)methyl 4-methylbenzenesulfonate (Intermediate 7H,7.9 mg, 0.030 mmol) was added followed by cesium carbonate (17 mg, 0.053mmol). The reaction was stirred at RT for 16 hours and then filtered andpurified by preparative HPLC (XBridge 30×50 mm 15-40% MeCN/H₂O (5 mMNH₄OH)) and further by FCC (0-5% MeOH(10% NH₄OH)/DCM) to afford thetitle compound (6.0 mg, 0.013 mmol).

LCMS: Rt: 2.15 min (LCMS Method 4) MS m/z 459.2 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.63 (s, 1H), 7.26-7.17 (m, 2H), 7.04-6.88 (m,2H), 4.84-4.72 (m, 4H), 4.35 (d, J=18.9 Hz, 2H), 4.12-3.93 (m, 4H),3.22-3.11 (m, 2H), 2.99 (m, 1H), 2.72 (m, 1H), 2.31 (dd, J=12.9, 7.3 Hz,1H), 2.21-1.93 (m, 5H), 1.88-1.54 (m, 6H).

Example 1I:(R)-2-(6-(4-(2-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole

(R)-2-(1-(2-(1,3,4-thiadiazol-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenol(Intermediate 5D, 9.9 mg, 0.027 mmol) was dissolved in DMF (0.3 mL) and4-(iodomethyl)tetrahydro-2H-pyran (7.3 mg, 0.032 mmol) was addedfollowed by cesium carbonate (17 mg, 0.053 mmol). The reaction wasstirred at RT for 48 hours and then incubated at 50° C. for 16 hr,filtered and purified by preparative HPLC (XBridge 30×50 mm 35-60%MeCN/H₂O (5 mM NH₄OH)) to afford the title compound (8.1 mg, 0.017mmol).

LCMS: Rt: 2.44 min (LCMS Method 4) MS m/z 469.2 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.63 (s, 1H), 7.21-7.07 (m, 2H), 6.89 (t,J=7.3 Hz, 2H), 4.14-3.93 (m, 6H), 3.85 (d, J=6.1 Hz, 2H), 3.49 (m, 2H),3.22-3.12 (m, 2H), 3.00 (m, 1H), 2.78-2.62 (m, 1H), 2.31 (dd, J=12.9,7.3 Hz, 1H), 2.20-1.91 (m, 6H), 1.89-1.45 (m, 10H).

Example 1J:(R)-2-(6-(4-(2-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole

(R)-2-(1-(2-(1,3,4-thiadiazol-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenol(Intermediate 7D, 12 mg, 0.033 mmol) was dissolved in DMF (0.3 mL) and4-(bromomethyl)-4-fluorotetrahydro-2H-pyran (7.8 mg, 0.040 mmol) wasadded followed by cesium carbonate (21 mg, 0.066 mmol). The reaction wasstirred at RT for 16 hours. Next, additional4-(bromomethyl)-4-fluorotetrahydro-2H-pyran (7.8 mg, 0.040 mmol) wasadded and the reaction was incubated at 50° C. for 24 hours, at 80° C.for 24 hours, at 100° C. for 96 hours, filtered and purified bypreparative HPLC (XBridge 30×50 mm 35-60% MeCN/H₂O (5 mM NH₄OH)) toafford the title compound (4.0 mg, 0.0081 mmol).

LCMS: Rt: 2.35 min (LCMS Method 4) MS m/z 487.2 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.63 (s, 1H), 7.17 (m, 2H), 6.93 (t, J=7.4 Hz,2H), 4.12-3.95 (m, 6H), 3.86 (m, 2H), 3.77 (m, 2H), 3.24-3.10 (m, 2H),3.02 (m, 1H), 2.71 (m, 1H), 2.31 (dd, J=12.9, 7.3 Hz, 1H), 2.19-1.55 (m,15H).

Example 1K:(R)-6-(4-(2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane

(R)-2-(1-(2-(pyrimidin-5-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenol(Intermediate 6G, 79 mg, 0.217 mmol), oxetan-3-yl4-methylbenzenesulfonate (43 mg, 0.188 mmol), and Cs₂CO₃ (246 mg, 0.754mmol) were dissolved in MeCN (5 mL) and the reaction was stirred at 80°C. for 16 hr. Additional oxetan-3-yl 4-methylbenzenesulfonate (28 mg,0.101) and MeCN (5 mL) were added and the reaction was stirred for anadditional 16 hr at 95° C. The solvent was then removed under reducedpressure and the crude mixture was diluted with EtOAc and washed withwater. The organic phase was separated, dried over MgSO₄ and the solventwas removed under reduced pressure. The residue was purified by FCC(0-10% MeOH (1% NH₄OH)/DCM) to afford the title compound (9.5 mg, 0.022mmol).

LCMS: Rt: 0.64 (LCMS Method 1) MS m/z 421.4 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.47 (s, 1H), 8.01 (s, 2H), 7.23 (dd, J=7.4,1.7 Hz, 1H), 7.12 (td, J=7.8, 1.8 Hz, 1H), 6.94 (t, J=7.4 Hz, 1H), 6.49(d, J=7.7 Hz, 1H), 5.28 (p, J=5.0 Hz, 1H), 5.03 (t, J=6.6 Hz, 2H), 4.70(dd, J=7.3, 4.8 Hz, 2H), 3.98-3.82 (m, 4H), 3.24 (d, J=10.6 Hz, 2H),3.07 (t, J=11.9 Hz, 1H), 2.82 (s, 1H), 2.38-2.19 (m, 3H), 2.12-1.95 (m,3H), 1.95-1.75 (m, 5H), 1.71-1.60 (m, 1H).

Example 1L:(R)-2-(pyrimidin-5-yl)-6-(4-(2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane

(R)-2-(1-(2-(pyrimidin-5-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenol(Intermediate 6G, 105 mg, 0.288 mmol), tetrahydro-2H-pyran-4-yl4-methylbenzenesulfonate (73.8 mg, 0.288 mmol), and Cs₂CO₃ (375 mg,1.152 mmol) were dissolved in MeCN (5 mL) and the solution was stirredat 80° C. for 16 hr. The solvent was then removed under reduced pressureand the crude mixture was diluted with EtOAc and washed with water. Theorganic phase was separated, dried over MgSO₄ and the solvent wasremoved under reduced pressure. The residue was purified by FCC (0-10%MeOH (1% NH₄OH)/DCM) and by preparative HPLC (XBridge 30×50 mm 35-60%MeCN/H₂O (5 mM NH₄OH), 75 mL/min) to afford the title compound (10.4 mg,0.023 mmol).

LCMS: Rt: 0.70 min (LCMS Method 1) MS m/z 449.5 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.47 (s, 1H), 8.00 (s, 2H), 7.27-7.03 (m, 2H),7.02-6.82 (m, 2H), 4.59 (m, 1H), 4.01-3.79 (m, 6H), 3.62 (m, 2H), 3.20(t, J=10.1 Hz, 2H), 3.05 (m, 1H), 2.76 (p, J=8.1 Hz, 1H), 2.31 (dd,J=12.8, 7.3 Hz, 1H), 2.18 (q, J=11.7 Hz, 2H), 2.02 (m, 5H), 1.90-1.55(m, 8H).

Example 1M:(R)-2-(pyrimidin-5-yl)-6-(4-(2-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane

(R)-2-(1-(2-(pyrimidin-5-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenol(Intermediate 6G, 80 mg, 0.219 mmol), (tetrahydro-2H-pyran-4-yl)methyl4-methylbenzenesulfonate (68.2 mg, 0.252 mmol), and Cs₂CO₃ (286 mg,0.878 mmol) were dissolved in MeCN (5 mL) and the reaction was stirredat 91° C. for 16 hr. The solvent was then removed under reduced pressureand the crude mixture was diluted with EtOAc and washed with water. Theorganic phase was separated, dried over MgSO₄ and the solvent wasremoved under reduced pressure. The residue was purified by FCC (0-10%MeOH (1% NH₄OH)/DCM) to afford the title compound (6.8 mg, 0.015 mmol).

LCMS: Rt: 0.74 min (LCMS Method 1) MS m/z 463.6 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.48 (s, 1H), 8.00 (s, 2H), 7.21-7.10 (m, 2H),6.90 (t, J=7.7 Hz, 2H), 4.04-3.81 (m, 7H), 3.49 (m, 2H), 3.34 (s, 2H),3.25 (s, 1H), 3.10-2.99 (m, 1H), 2.86 (t, J=8.4 Hz, 1H), 2.38-2.23 (m,3H), 2.16-1.92 (m, 4H), 1.92-1.44 (m, 10H).

Example 1N:(R)-6-(4-(2-(oxetan-3-ylmethoxy)phenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane

(R)-2-(1-(2-(pyrimidin-5-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenol(Intermediate 6G, 80 mg, 0.219 mmol), 3-(iodomethyl)oxetane (50 mg,0.252 mmol) and Cs₂CO₃ (286 mg, 0.878 mmol) were dissolved in MeCN (5mL) and the solution was stirred at 90° C. for 16 hr. The solvent wasthen removed under reduced pressure and the crude mixture was dilutedwith EtOAc and washed with water. The organic phase was separated, driedover MgSO₄ and the solvent was removed under reduced pressure. Theresidue was next purified by FCC (0-10% MeOH (1% NH₄OH)/DCM) and furtherby preparative HPLC (XBridge 30×50 mm 35-60% MeCN/H₂O (5 mM NH₄OH), 75mL/min) to afford the title compound (4.5 mg, 0.103 mmol).

LCMS: Rt: 1.14 min (LCMS Method 3) MS m/z 435.5 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.47 (s, 1H), 8.00 (s, 2H), 7.27-7.07 (m, 2H),7.00-6.82 (m, 2H), 4.89 (dd, J=8.0, 6.1 Hz, 2H), 4.66 (t, J=6.1 Hz, 2H),4.18 (d, J=5.6 Hz, 2H), 3.96-3.81 (m, 4H), 3.49 (m, 1H), 3.18 (s, 2H),3.04 (m, 1H), 2.75 (s, 1H), 2.30 (dd, J=12.9, 7.2 Hz, 1H), 2.19 (s, 2H),2.10-1.92 (m, 3H), 1.90-1.56 (m, 6H).

Example 10:(R)-6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)phenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane

(R)-2-(1-(2-(pyrimidin-5-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenol(Intermediate 6G, 80 mg, 0.219 mmol), 2-oxaspiro[3.3]heptan-6-yl4-methylbenzenesulfonate (Intermediate 7A, 67.7 mg, 0.252 mmol), andCs₂CO₃ (286 mg, 0.878 mmol) was dissolved in MeCN (5 mL) and thesolution was stirred at 95° C. for 16 hr. The solvent was then removedunder reduced pressure and the crude mixture was diluted with EtOAc andwashed with water. The organic phase was separated, dried over MgSO₄ andthe solvent was removed under reduced pressure. The residue was purifiedby FCC (0-10% MeOH (1% NH₄OH)/DCM) to afford the title compound (10.6mg, 0.203 mmol).

LCMS: Rt: 0.67 min (LCMS Method 1) MS m/z 461.4 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.47 (s, 1H), 8.00 (s, 2H), 7.22-7.04 (m, 2H),6.88 (t, J=7.4 Hz, 1H), 6.72 (d, J=8.2 Hz, 1H), 4.76 (s, 2H), 4.68 (s,2H), 4.57 (p, J=6.6 Hz, 1H), 3.97-3.81 (m, 4H), 3.18 (s, 2H), 3.02-2.88(m, 1H), 2.86-2.72 (m, 3H), 2.36-2.26 (m, 3H), 2.18 (s, 2H), 2.11-1.92(m, 3H), 1.87-1.57 (m, 6H).

Example 1P:(R)-2-(pyrimidin-5-yl)-6-(4-(2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane

(R)-2-(1-(2-(pyrimidin-5-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenol(Intermediate 6G, 80 mg, 0.219 mmol), (S)-tetrahydrofuran-3-yl4-methylbenzenesulfonate (Intermediate 7C, 61.2 mg, 0.252 mmol), andCs₂CO₃ (286 mg, 0.878 mmol) were dissolved in MeCN (5 mL) to give ayellow solution. The solution was stirred at 95° C. for 16 hrs and thesolvent was then removed under reduced pressure. The crude mixture wasdiluted with EtOAc and washed with water. The organic phase wasseparated, dried over MgSO₄ and the solvent was removed under reducedpressure. The residue was purified by FCC (0-10% MeOH (1% 7N NH₃ inMeOH)/DCM) and preparative HPLC (XBridge 30×50 mm 35-60% MeCN/H₂O (5 mMNH₄OH)) to afford the title compound (16 mg, 0.036 mmol).

LCMS: Rt: 0.64 min (LCMS Method 1) MS m/z 435.5. [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.47 (s, 1H), 8.00 (s, 2H), 7.23-7.12 (m, 2H),6.95-6.87 (m, 2H), 5.09-5.02 (m, 1H), 4.01-3.81 (m, 8H), 3.22 (s, 3H),3.00 (s, 1H), 2.81 (s, 1H), 2.39-2.20 (m, 3H), 2.16-1.92 (m, 4H),1.89-1.56 (m, 6H).

Example 2A:(R)-1-(2-(1-(2-(1,3,4-oxadiazol-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)-2-methylpropan-2-ol

(R)-1-(2-(1-(2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)-2-methylpropan-2-ol(Intermediate 4C, 65 mg, 0.21 mmol), ethyl5-bromo-1,3,4-oxadiazole-2-carboxylate (46 mg, 0.21 mmol), and potassiumphosphate (44 mg, 0.21 mmol) were suspended in a mixture of 2% aqueousTPGS-750-M (0.38 mL), and THE (0.042 mL). The reaction was stirred at RTfor 16 hr, and then the mixture was extracted with DCM, and the combinedorganic layers were concentrated. The residue was purified by FCC (0-7%MeOH/DCM). The obtained intermediate (66 mg, 0.13 mmol) was dissolved inMeOH (1.3 mL), and a 2M solution of LiOH (0.59 mL, 1.2 mmol) was added.The reaction was stirred at RT for 4 hours, and a 4N HCl solution wasadded to adjust pH<3. The reaction was stirred at RT for 16 hr,concentrated, and purified by preparative HPLC (XBridge 30×50 mm 25-50%MeCN/H₂O (5 mM NH₄OH)) to afford the title compound (31 mg, 0.070 mmol).

LCMS: Rt: 2.06 min (LCMS Method 4) MS m/z 427.2 [M+H]⁺.

¹H NMR (DMSO-d₆) δ 8.62 (s, 1H), 7.19-7.08 (m, 2H), 6.93-6.83 (m, 2H),4.63 (s, 1H), 4.03-3.86 (m, 4H), 3.67 (s, 2H), 3.08-2.97 (m, 2H),2.95-2.82 (m, 1H), 2.64-2.54 (m, 1H), 2.13 (dd, J=12.7, 6.8 Hz, 1H),2.04-1.78 (m, 5H), 1.77-1.65 (m, 3H), 1.64-1.37 (m, 3H), 1.23 (s, 6H).

Example 2B:2-((R)-6-(4-(2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole

(R)-6-(4-(2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 4D, 144 mg, 0.404 mmol), ethyl5-bromo-1,3,4-oxadiazole-2-carboxylate (89 mg, 0.40 mmol), and potassiumphosphate (257 mg, 1.21 mmol) were suspended in a mixture of 2% aqueousTPGS-750-M (0.73 mL), and THF (0.081 mL). The reaction was treatedsimilarly to Example 2A and the product was purified by FCC (0-7%MeOH/DCM), and by preparative HPLC (XBridge 30×50 mm 35-60% MeCN/H₂O (5mM NH₄OH)) to afford the title compound (38 mg, 0.086 mmol).

LCMS: Rt: 2.15 min (LCMS Method 4) MS m/z 425.3 [M+H]⁺.

¹H NMR (DMSO-d₆) δ 8.62 (s, 1H), 7.20-7.10 (m, 2H), 6.95-6.85 (m, 2H),5.07-5.00 (m, 1H), 4.02-3.85 (m, 5H), 3.84-3.71 (m, 3H), 3.08-2.95 (m,2H), 2.87-2.74 (m, 1H), 2.65-2.54 (m, 1H), 2.25-2.09 (m, 2H), 2.04-1.87(m, 4H), 1.87-1.77 (m, 2H), 1.76-1.64 (m, 3H), 1.63-1.51 (m, 2H),1.51-1.40 (m, 1H).

Example 2C: (R)-ethyl5-(6-(4-(2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole-2-carboxylate

(R)-6-(4-(2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 4E, 86 mg, 0.25 mmol), ethyl5-bromo-1,3,4-oxadiazole-2-carboxylate (55 mg, 0.25 mmol), and potassiumphosphate (53 mg, 0.25 mmol) were suspended in a mixture of 2% aqueousTPGS-750-M (0.50 mL), and THE (0.05 mL). The reaction was treatedsimilarly to Example 2A and the product was purified by preparative HPLC(XBridge 30×50 mm 25-50% MeCN/H₂O (5 mM NH₄OH)), and by FCC (0-10%MeOH/DCM) to afford the title compound (18 mg, 0.043 mmol). LCMS: Rt:2.16 min (LCMS Method 4) MS m/z 413.3 [M+H]⁺.

¹H NMR (DMSO-d₆) δ 8.62 (s, 1H), 7.18-7.10 (m, 2H), 6.96-6.86 (m, 2H),4.11-4.06 (m, 2H), 4.01-3.87 (m, 4H), 3.69-3.65 (m, 2H), 3.33 (s, 3H),3.07-2.95 (m, 2H), 2.93-2.80 (m, 1H), 2.64-2.53 (m, 1H), 2.18-2.08 (m,1H), 2.03-1.79 (m, 5H), 1.76-1.66 (m, 3H), 1.65-1.51 (m, 2H), 1.50-1.41(m, 1H).

Example 2D:(R)-2-(6-(4-(2-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole

(R)-6-(4-(2-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 4F, 58 mg, 0.14 mmol), ethyl5-bromo-1,3,4-oxadiazole-2-carboxylate (35 mg, 0.16 mmol), and potassiumphosphate (34 mg, 0.16 mmol) were suspended in a mixture of 2% aqueousTPGS-750-M (0.26 mL), and THE (0.029 mL). The reaction was treatedsimilarly to Example 2A and the product was purified by preparative HPLC(XBridge 30×50 mm 35-60% MeCN/H₂O (5 mM NH₄OH)) to afford the titlecompound (18 mg, 0.039 mmol).

LCMS: Rt: 1.18 min (LCMS Method 3) MS m/z 471.0 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.36 (s, 1H), 7.23-7.08 (m, 2H), 6.93 (t,J=7.5 Hz, 2H), 4.14-3.97 (m, 6H), 3.86 (m, 2H), 3.77 (m, 2H), 3.21-3.11(m, 2H), 3.01 (m, 1H), 2.75-2.63 (m, 1H), 2.29 (dd, J=12.9, 7.3 Hz, 1H),2.19-1.52 (m, 15H).

Example 2E:(R)-2-(6-(4-(2-((4-methyltetrahydro-2H-pyran-4-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole

(R)-6-(4-(2-((4-methyltetrahydro-2H-pyran-4-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 4G, 56 mg, 0.14 mmol), ethyl5-bromo-1,3,4-oxadiazole-2-carboxylate (34 mg, 0.16 mmol), and potassiumphosphate (33 mg, 0.16 mmol) were suspended in a mixture of 2% aqueousTPGS-750-M (0.26 mL), and THE (0.03 mL). The reaction was treatedsimilarly to Example 2A and the product was purified by preparative HPLC(XBridge 30×50 mm 35-60% MeCN/H₂O (5 mM NH₄OH)) to afford the titlecompound (16 mg, 0.033 mmol).

LCMS: Rt: 2.49 min (LCMS Method 3) MS m/z 467.4 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.36 (s, 1H), 7.23-7.11 (m, 2H), 6.95-6.84 (m,2H), 4.13-3.97 (m, 4H), 3.83-3.64 (m, 6H), 3.17 (d, J=8.8 Hz, 2H), 3.02(m, 1H), 2.73-2.63 (m, 1H), 2.29 (dd, J=12.9, 7.3 Hz, 1H), 2.18-1.93 (m,5H), 1.89-1.64 (m, 7H), 1.58 (m, 1H), 1.45 (m, 3.4 Hz, 2H), 1.20 (s,3H).

Example 2F:(R)-2-(6-(4-(2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole

(R)-6-(4-(2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 4H, 108 mg, 0.291 mmol), ethyl5-bromo-1,3,4-oxadiazole-2-carboxylate (64 mg, 0.29 mmol), and potassiumphosphate (186 mg, 0.874 mmol) were suspended in a mixture of 2% aqueousTPGS-750-M (0.53 mL), and THE (0.06 mL). The reaction was treatedsimilarly to Example 2A and the product was purified by FCC (0-10%MeOH/DCM), and by preparative HPLC (XBridge 30×50 mm 35-60% MeCN/H₂O (5mM NH₄OH)) to afford the title compound (57 mg, 0.13 mmol).

LCMS: Rt: 2.23 min (LCMS Method 4) MS m/z 439.2 [M+H]⁺.

¹H NMR (DMSO-d₆) δ 8.62 (s, 1H), 7.22-7.07 (m, 2H), 6.99 (d, J=7.8 Hz,1H), 6.92-6.82 (m, 1H), 4.66-4.51 (m, 1H), 4.03-3.86 (m, 4H), 3.85-3.75(m, 2H), 3.57-3.45 (m, 2H), 3.08-2.96 (m, 2H), 2.93-2.81 (m, 1H),2.64-2.53 (m, 1H), 2.13 (dd, J=12.7, 6.8 Hz, 1H), 2.05-1.90 (m, 5H),1.89-1.77 (m, 2H), 1.76-1.66 (m, 3H), 1.66-1.55 (m, 4H), 1.51-1.40 (m,1H).

Example 2G:(R)-2-(6-(4-(2-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole

(R)-ethyl5-(6-(4-(2-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole-2-carboxylate(Intermediate 41, 119 mg, 0.309 mmol), ethyl5-bromo-1,3,4-oxadiazole-2-carboxylate (68 mg, 0.31 mmol), and potassiumphosphate (66 mg, 0.31 mmol) were suspended in a mixture of 2% aqueousTPGS-750-M (0.56 mL), and THE (0.06 mL). The reaction was treatedsimilarly to Example 2A and the product was purified by preparative HPLC(XBridge 30×50 mm 35-60% MeCN/H₂O (5 mM NH₄OH)) to afford the titlecompound (50 mg, 0.11 mmol).

LCMS: Rt: 2.38 min (LCMS Method 4) MS m/z 453.2 [M+H]⁺.

¹H NMR (DMSO-d₆) δ 8.62 (s, 1H), 7.20-7.08 (m, 2H), 6.96-6.82 (m, 2H),4.02-3.78 (m, 8H), 3.40-3.34 (m, 2H), 3.07-2.95 (m, 2H), 2.89-2.78 (m,1H), 2.62-2.54 (m, 1H), 2.18-2.09 (m, 1H), 2.07-1.77 (m, 6H), 1.75-1.64(m, 5H), 1.63-1.49 (m, 2H), 1.49-1.31 (m, 3H).

Example 2H:(R)-2-(6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole

(R)-6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 4Y, 27 mg, 0.076 mmol), ethyl5-bromo-1,3,4-oxadiazole-2-carboxylate (18 mg, 0.084 mmol), andpotassium phosphate (18 mg, 0.084 mmol) were suspended in a mixture 2%aqueous TPGS-750-M (0.14 mL) and THE (0.02 mL). The reaction was stirredat RT for 16 hours and then MeOH (1 mL) was added followed by water (0.5mL) and LiOH (25 mg, 0.61 mmol). The reaction was stirred at RT for 2hours, and then a 6M solution of HCl was added until the was pH<2. Thereaction was stirred at RT for 1 hour and then concentrated and basifiedwith a saturated solution of sodium carbonate. The solution wasextracted with EtOAc, and the combined organic layers were concentrated.The residue was purified by preparative HPLC (XBridge 30×50 mm 10-30%MeCN/H₂O (0.1% formic acid)) to afford the title compound (6.8 mg, 0.014mmol) as a white solid.

LCMS: Rt: 2.15 min (LCMS Method 4) MS m/z 423.4 [M+H]⁺.

¹H NMR (DMSO-d₆) δ 8.64 (s, 1H), 7.27-7.20 (m, 2H), 7.18-7.11 (m, 2H),4.03-3.88 (m, 6H), 3.53-3.43 (m, 2H), 3.11-2.96 (m, 3H), 2.87-2.73 (m,1H), 2.70-2.57 (m, 1H), 2.21-2.10 (m, 1H), 2.10-1.98 (m, 2H), 1.98-1.87(m, 1H), 1.87-1.78 (m, 2H), 1.77-1.58 (m, 7H), 1.58-1.50 (m, 2H),1.50-1.42 (m, 1H).

Example 21:(R)-2-(6-(4-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole

(R)-6-(4-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 4K, 47 mg, 0.10 mmol), ethyl5-bromo-1,3,4-oxadiazole-2-carboxylate (27 mg, 0.12 mmol) and potassiumphosphate (24 mg, 0.11 mmol) were suspended in a mixture 2% aqueousTPGS-750-M (1.8 mL) and THE (0.20 mL). The reaction was stirred at RTfor 16 hours and then MeOH (0.5 mL) was added followed by water (0.5 mL)and LiOH (34 mg, 0.81 mmol). The reaction was stirred at RT for 2 hoursand then a 6M solution of HCl was added until the pH<2. The reaction wasstirred at RT for 1 hour, concentrated and basified with a saturatedsolution of sodium carbonate. The solution was then extracted withEtOAc, and the combined organic layers were concentrated. The residuewas purified by preparative HPLC (XBridge 30×50 mm 35-60% MeCN/H₂O (5 mMNH₄OH)) and by FCC (0-5% MeOH(1% NH₃ in MeOH)/DCM) to afford the titlecompound (5.8 mg, 0.013 mmol) as a beige solid.

LCMS: Rt: 2.17 min (LCMS Method 4) MS m/z 441.3 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.36 (s, 1H), 7.27 (dd, J=8.7, 6.0 Hz, 1H),6.97 (dd, J=10.9, 2.8 Hz, 1H), 6.90 (td, J=8.4, 2.7 Hz, 1H), 4.17-3.98(m, 6H), 3.59 (m, 2H), 3.25-3.16 (m, 2H), 3.07 (m, 1H), 2.94 (m, 1H),2.87-2.73 (m, 1H), 2.39-2.18 (m, 3H), 2.11-1.93 (m, 3H), 1.91-1.73 (m,7H), 1.68-1.56 (m, 3H).

Example 2J:2-((6R)-6-(4-(5-fluoro-2-(tetrahydrofuran-3-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole

(6R)-6-(4-(5-fluoro-2-(tetrahydrofuran-3-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 4L, 52 mg, 0.12 mmol), ethyl5-bromo-1,3,4-oxadiazole-2-carboxylate (31 mg, 0.14 mmol) and potassiumphosphate (30 mg, 0.14 mmol) were suspended in a mixture 2% aqueousTPGS-750-M (0.21 mL) and THF (0.023 mL). The reaction was stirred at RTfor 16 hours and then MeOH (0.5 mL) was added followed by water (0.5 mL)and LiOH (39 mg, 0.93 mmol). The reaction was stirred at RT for 2 hoursand then a 6M solution of HCl was added until the pH<2. The reaction wasstirred at RT for 1 hour, concentrated and it was then basified with asaturated solution of sodium carbonate. The reaction was extracted withEtOAc, and the combined organic layers were concentrated. The residuewas purified by preparative HPLC (XBridge 30×50 mm 25-50% MeCN/H₂O (5 mMNH₄OH)) and further by FCC (0-5% MeOH(1% NH₃ in MeOH)/DCM) to afford thetitle compound (6.1 mg, 0.014 mmol) as a mixture of diastereomers.

LCMS: Rt: 2.11 min (LCMS Method 4) MS m/z 427.4 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.36 (s, 1H), 7.32 (dd, J=8.7, 5.9 Hz, 1H),6.98 (dd, J=10.8, 2.8 Hz, 1H), 6.91 (m, 1H), 4.16-3.98 (m, 6H), 3.90 (q,J=7.6 Hz, 1H), 3.75-3.65 (m, 2H), 3.25-3.16 (m, 2H), 2.97 (m, 1H), 2.78(m, 1H), 2.41-2.20 (m, 4H), 2.11-1.89 (m, 4H), 1.88-1.74 (m, 5H),1.68-1.56 (m, 1H).

Example 2K:2-((6R)-6-(4-(2-(tetrahydrofuran-3-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole

(6R)-6-(4-(2-(tetrahydrofuran-3-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 4M, 50 mg, 0.12 mmol), ethyl5-bromo-1,3,4-oxadiazole-2-carboxylate (31 mg, 0.14 mmol) and potassiumphosphate (30 mg, 0.14 mmol) were suspended in a mixture 2% aqueousTPGS-750-M (0.21 mL) and THF (0.023 mL). The reaction was stirred at RTfor 16 hours and then MeOH (0.5 mL) was added followed by water (0.5 mL)and LiOH (39 mg, 0.93 mmol). The reaction was stirred at RT for 2 hoursand then a 6M solution of HCl (0.29 mL) was added until the pH<2. Thereaction was stirred at RT for 1 hour, concentrated and basified with asaturated solution of sodium carbonate. The solution was then extractedwith EtOAc, and the combined organic layers were concentrated. Theresidue was purified by preparative HPLC (XBridge 30×50 mm 25-50%MeCN/H₂O (5 mM NH₄OH)) and further by FCC (0-5% MeOH(1% NH₃ inMeOH)/DCM) to afford the title compound (6.4 mg, 0.015 mmol) as amixture of diastereomers.

LCMS: Rt: 2.00 min (LCMS Method 4) MS m/z 409.4 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.36 (s, 1H), 7.33-7.28 (m, 1H), 7.28-7.23 (m,1H), 7.21-7.14 (m, 2H), 4.15-3.98 (m, 6H), 3.91 (q, J=7.6 Hz, 1H),3.79-3.67 (m, 2H), 3.24-3.14 (m, 2H), 2.95 (m, 1H), 2.76 (m, 1H),2.41-2.17 (m, 4H), 2.12-1.93 (m, 4H), 1.90-1.72 (m, 5H), 1.67-1.54 (m,1H).

Example 2L:(R)-2-(6-(4-(2-((tetrahydro-2H-pyran-4-yl)methyl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole

Step 1: tert-butyl(R)-6-(4-(2-(((trifluoromethyl)sulfonyl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate

tert-butyl(R)-6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate(Intermediate 6C, 300 mg, 0.776 mmol) was dissolved in DCM (7 mL) andpyridine (0.13 mL, 1.5 mmol) was added. The reaction was cooled to 0° C.and a solution of Tf₂O in DCM (1M, 0.85 mL, 0.85 mmol) was added. Thereaction was stirred at RT for 1 hour then cooled at 0° C., and pyridine(0.038 mL, 0.47 mmol) was added followed by additional Tf₂O in DCM (1M,0.23 mL, 0.23 mmol). The reaction was stirred at RT 1 hour, neutralizedwith a saturated solution of sodium bicarbonate, extracted 3 times withDCM, and the combined organic layers were dried with magnesium sulfate,filtered and concentrated. The residue was purified by FCC (0-10%MeOH/DCM) to afford the title compound (333 mg, 0.642 mmol).

LCMS: Rt: 1.36 min (LCMS Method 2) MS m/z 519.2 [M+H]⁺.

Step 2: 4-(bromomethylene)tetrahydro-2H-pyran

To a suspension of (bromomethyl)triphenylphosphonium bromide (1.13 g,2.60 mmol) in THE (10 mL) at −78° C. was added potassium tert-butoxide(291 mg, 2.60 mmol). The reaction was stirred at 0° C. for 1 hour, andthen a solution of tetrahydro-4H-pyran-4-one (200 mg, 2.00 mmol) in THE(10 mL) was added. The reaction was then stirred at 0° C. for 16 hr.Additional (bromomethyl)triphenylphosphonium bromide (261 mg, 0.599mmol), and potassium tert-butoxide (67 mg, 0.60 mmol) were added. Thereaction was stirred at RT for 4 hours, and the reaction wasconcentrated under reduced pressure. Water was added and the aqueouslayer was extracted with diethyl ether (3×). The combined organic layerswere dried with MgSO₄, filtered, and concentrated under reducedpressure. The residue was purified by FCC (0-10% EtOAc/heptanes) toafford the title intermediate (162 mg, 0.641 mmol).

¹H NMR (400 MHz, CD₂Cl₂) δ 5.89 (t, J=1.2 Hz, 1H), 3.61-3.53 (m, 4H),2.37-2.28 (m, 2H), 2.24-2.15 (m, 2H).

Step 3: tert-butyl(R)-6-(4-(2-((tetrahydro-4H-pyran-4-ylidene)methyl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate

To an oven-dried glass vessel was added XPhosPd G2 (15.17 mg, 0.019mmol), XPhos (18.76 mg, 0.039 mmol), tetrahydroxydiboron (51.9 mg, 0.578mmol) and potassium acetate (34.7 mg, 0.578 mmol). The vessel was sealedand then evacuated and back-filled with N₂ gas (the process was repeatedfour times). EtOH (3 mL) was added via syringe and tert-butyl(R)-6-(4-(2-(((trifluoromethyl)sulfonyl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate(100 mg, 0.193 mmol) in EtOH (2 mL) was added via syringe. The reactionmixture was then stirred at 80° C. for 2 hr. Next, K₂CO₃ (93 mg, 0.675mmol) dissolved in degassed water (3.0 mL) was added into the abovereaction solution, followed by the addition of4-(bromomethylene)tetrahydro-2H-pyran (51.2 mg, 0.289 mmol) in THE (1.5mL). The reaction mixture was stirred at 80° C. for 16 hours. Thereaction was diluted with EtOAc and water and the layers were separatedand the organic layer was dried over sodium sulfate, filtered andconcentrated. The residue was then purified by FCC (0-60% EtOAc (1% 7NNH₃ in MeOH)/heptanes) to yield the title compound (90 mg, 0.193 mmol).

LCMS: Rt: 0.85 min (LCMS Method 1) MS m/z 467.5 [M+H]⁺.

Step 4: tert-butyl(R)-6-(4-(2-((tetrahydro-2H-pyran-4-yl)methyl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate

tert-butyl(R)-6-(4-(2-((tetrahydro-4H-pyran-4-ylidene)methyl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate(90 mg, 0.19 mmol) was dissolved in ethanol (10 mL) and 20% wet Pd(OH)₂(27 mg, 0.029 mmol) was added. The reaction was stirred under a hydrogenballoon at RT for 16 hr, and then filtered and concentrated. The residuewas purified by FCC (0-80% EtOAc/heptanes) to afford the titleintermediate (70 mg, 0.11 mmol).

LCMS: Rt: 1.33 min (LCMS Method 2) MS m/z 469.6 [M+H]⁺.

Step 5:(R)-6-(4-(2-((tetrahydro-2H-pyran-4-yl)methyl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane

To a solution of tert-butyl(R)-6-(4-(2-((tetrahydro-2H-pyran-4-yl)methyl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate(70 mg, 0.149 mmol) in DCM (2 mL) was added TFA (1 mL, 0.149 mmol). Thereaction solution was stirred at RT for 2 hr. The solvent was thenremoved and the product was used without further purification (70 mg,0.15 mmol).

LCMS: Rt: 0.58 min (LCMS Method 2) MS m/z 369 [M+H]⁺.

Step 6:(R)-2-(6-(4-(2-((tetrahydro-2H-pyran-4-yl)methyl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole

(R)-6-(4-(2-((tetrahydro-2H-pyran-4-yl)methyl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(70 mg, 0.15 mmol), ethyl 5-bromo-1,3,4-oxadiazole-2-carboxylate (38 mg,0.17 mmol) were dissolved in THF (4.0 mL) and DIPEA (0.076 mL, 0.44mmol) was added. The reaction was stirred at RT for 2 hours, then a 2Msolution of LiOH (2.0 mL, 4.0 mmol) was added followed by MeOH (1 mL).The reaction was stirred at RT for 2 hours, then a 4M solution of HCl(˜3 mL) was added until pH<2. The reaction was stirred at RT for 3hours, then basified with a 7N solution of NH₃ in MeOH, concentrated,extracted with DCM (3×), and the combined organic layers wereconcentrated. The residue was purified by preparative HPLC (XBridgePeptide BEH C18 19×150 mm 40-55% MeCN/H₂O (10 mM NH₄OH)), and bypreparative HPLC (XSelect CSH C18 5 μm 19×150 mm 20-35% MeCN/H₂O (0.1%TFA)). The residue was dissolved in MeOH and the solution was passedthrough an Agilent PL-HCO3 MP resin ion-exchange column, eluting withMeOH. The obtained freebase was purified by FCC (0-6% MeOH/DCM) toafford the title compound (9.0 mg, 0.020 mmol).

LCMS: Rt: 2.31 min (LCMS Method 4) MS m/z 437.7 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.37 (s, 1H), 7.30-7.24 (m, 1H), 7.19-7.13 (m,1H), 7.12-7.05 (m, 2H), 4.17-3.96 (m, 4H), 3.91 (m, 2H), 3.38-3.32 (m,2H), 3.21 (d, J=11.5 Hz, 2H), 2.89-2.71 (m, 2H), 2.62 (d, J=7.3 Hz, 2H),2.33 (dd, J=13.1, 7.4 Hz, 1H), 2.22 (s, 2H), 2.11-1.92 (m, 3H),1.90-1.47 (m, 9H), 1.35 (m, 2H).

Example 2M:(R)-2-(6-(4-(2-(oxazol-2-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole

Step 1: tert-butyl(R)-6-(4-(2-(oxazol-2-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate

To an oven-dried glass microwave vial, XPhos Pd G2 (21 mg, 0.027 mmol),XPhos (26 mg, 0.054 mmol), tetrahydroxydiboron (73 mg, 0.81 mmol), andpotassium acetate (49 mg, 0.81 mmol) were added. The vessel was sealed,then evacuated and back-filled with nitrogen gas (the process wasrepeated four times). EtOH (3 mL) was added via syringe, followed by asolution of a tert-butyl(R)-6-(4-(2-(((trifluoromethyl)sulfonyl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate(Example 2L, Step 1, 140 mg, 0.270 mmol) in EtOH (3 mL). The reactionmixture was stirred at 80° C. for 2 hours and then potassium carbonate(112 mg, 0.81 mmol) in water (3 mL, degassed) was added, followed by asolution of 2-bromo-1,3-oxazole (63 mg, 0.41 mmol) in THE (3 mL,degassed). The reaction mixture was stirred at 80° C. for 16 hr, thenfiltered and concentrated under reduced pressure. The residue waspurified by FCC (0-100% EtOAc (1% 7N NH₃ in MeOH)/heptanes) to affordthe title intermediate (47 mg, 0.11 mmol).

LCMS: Rt: 1.23 min (LCMS Method 2), MS m/z 438.8 [M+H]⁺.

Step 2:(R)-2-(2-(1-(2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenyl)oxazole

tert-butyl(R)-6-(4-(2-(oxazol-2-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate(22 mg, 0.050 mmol) was dissolved in DCM (1 mL) and TFA (0.2 mL) wasadded. The reaction was stirred at RT for 2 hours, concentrated, dilutedwith DCM, basified with a saturated solution of sodium bicarbonate andextracted with DCM (3×). The combined organic layers were dried withmagnesium sulfate, filtered and concentrated to afford the titleintermediate (17 mg, 0.050 mmol).

LCMS: Rt: 0.54 min (LCMS Method 1) MS m/z 338.6 [M+H]⁺.

Step 3:(R)-2-(6-(4-(2-(oxazol-2-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole

(R)-2-(2-(1-(2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenyl)oxazole (17mg, 0.050 mmol), ethyl 5-bromo-1,3,4-oxadiazole-2-carboxylate (14 mg,0.065 mmol) and potassium phosphate (14 mg, 0.065 mmol) were suspendedin a mixture 2% aqueous TPGS-750-M (0.30 mL) and THE (0.030 mL). Thereaction was stirred at RT for 16 hr, then a 2M solution of LiGH (2.2mL, 4.4 mmol) was added The reaction was stirred at RT for 2 hours, thena 4M solution of HCl was added until pH<2. The reaction was stirred atRT for 3 hours, basified with a saturated solution of sodiumbicarbonate, extracted 3 times with ethyl acetate, and the combinedorganic layers were concentrated. The residue was purified bypreparative HPLC (XBridge Peptide BEH C18 19×150 mm 40-55% MeCN/H₂O (10mM NH₄OH)) to afford the title compound (4.0 mg, 0.0095 mmol).

LCMS: Rt: 2.05 min (LCMS Method 4) MS m/z 406.4 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.36 (s, 1H), 8.01 (s, 1H), 7.81-7.68 (m, 1H),7.57-7.44 (m, 2H), 7.37-7.23 (m, 2H), 4.20-3.81 (m, 4H), 3.46 (m, 1H),3.21-3.05 (m, 2H), 2.70 (m, 1H), 2.29 (dd, J=13.2, 7.4 Hz, 1H),2.17-1.92 (m, 5H), 1.82 (m, 5H), 1.66-1.47 (m, 1H).

Example 2N:(1S,4s)-4-(2-(1-((R)-2-(1,3,4-oxadiazol-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenyl)cyclohexan-1-olor(1R,4r)-4-(2-(1-((R)-2-(1,3,4-oxadiazol-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenyl)cyclohexan-1-oland Example 2O:(1s,4r)-4-(2-(1-((R)-2-(1,3,4-oxadiazol-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenyl)cyclohexan-1-olor(1r,4r)-4-(2-(1-((R)-2-(1,3,4-oxadiazol-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenyl)cyclohexan-1-ol

Step 1: tert-butyl(6R)-6-(4-(4′-hydroxy-2′,3′,4′,5′-tetrahydro-[1,1′-biphenyl]-2-yl)piperidin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate

To a THF (3 mL) solution of tert-butyl(6R)-6-(4-(4′-((tert-butyldimethylsilyl)oxy)-2′,3′,4′,5′-tetrahydro-[1,1′-biphenyl]-2-yl)piperidin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate(Intermediate 9E, 259 mg, 0.446 mmol) was added TBAF in THE (1M, 0.580mL, 0.580 mmol). The reaction mixture was stirred for 16 hours. Next,additional TBAF in THF (1M, 0.580 mL, 0.580 mmol) was added and thereaction was stirred for 24 hours. Next, additional TBAF in THE (1M,0.580 mL, 0.580 mmol) was added to the reaction and it was stirred at50° C. for 3 hr. The reaction was then concentrated and purified by FCC(0-8% 7N NH₃ MeOH in 32% EtOAc/heptanes) to yield the title compound(173 mg, 0.367 mmol).

LCMS: Rt: 1.23 min (LCMS Method 2) MS m/z 467.4 [M+H]⁺.

Step 2: tert-butyl(R)-6-(4-(2-(4-hydroxycyclohexyl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate

To a MeOH (3.7 mL) solution of tert-butyl(6R)-6-(4-(4′-hydroxy-2′,3′,4′,5′-tetrahydro-[1,1′-biphenyl]-2-yl)piperidin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate(173 mg, 0.371 mmol), was added Pd—C(3.95 mg, 0.037 mmol). The reactionmixture was stirred under a H₂ balloon for 72 hours. The crude wasfiltered and concentrated under reduced pressure. The residue waspurified by FCC (0-8% 7N NH₃ in MeOH/32% EtOAc/heptanes) to yield thetitle compound as a yellow solid (145 mg, 0.248 mmol).

LCMS: Rt: 1.21 min (LCMS Method 2) MS m/z 469.5 [M+H]⁺.

Step 3:(R)-4-(2-(1-(2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenyl)cyclohexan-1-ol

tert-butyl(R)-6-(4-(2-(4-hydroxycyclohexyl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate(145 mg, 0.248 mmol) was dissolved in DCM (0.75 mL) and TFA (0.48 mL,6.19 mmol) and the reaction was stirred for 3 hours. The reaction wasthen concentrated and dissolved in DCM and washed with 1N NaOH to yieldthe title compound that was used without further purification (90 mg,0.122 mmol).

LCMS: Rt: 0.79 min (LCMS Method 2) MS m/z 369.4 [M+H]⁺.

Step 4:(1S,4s)-4-(2-(1-((R)-2-(1,3,4-oxadiazol-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenyl)cyclohexan-1-oland(1R,4r)-4-(2-(1-((R)-2-(1,3,4-oxadiazol-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenyl)cyclohexan-1-ol

To a THF (1 mL) solution of(R)-4-(2-(1-(2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenyl)cyclohexan-1-ol(90 mg, 0.122 mmol) and ethyl 5-bromo-1,3,4-oxadiazole-2-carboxylate(40.5 mg, 0.147 mmol) was added DIPEA (0.047 mL, 0.269 mmol) at 0° C.The reaction was stirred for 2 hr and then it was concentrated anddiluted with EtOAc and washed with water and brine. The organic layerwas dried over magnesium sulfate, filtered and concentrated. The residuewas dissolved in THE (1 mL) and LiGH (30.7 mg, 0.733 mmol) dissolved inwater (1 mL) was added. The reaction was stirred for 72 hours. Thereaction was then cooled to −5° C. and 4N HCl (0.203 mL, 1.221 mmol) wasadded and the reaction was warmed to RT and stirred for 2 hours. Aqsodium carbonate was added until the pH was greater than 9 and thereaction was concentrated and diluted with EtOAc. The organic layer waswashed with brine, dried over magnesium sulfate, filtered andconcentrated. The crude was then purified by FCC (0-5% 7N NH₃ inMeOH/32% EtOAc/heptanes) and further by preparative HPLC (XBridge C₁₈OBD 30×50 mm, MeCN/H₂O+5 mM NH₄OH, 75 mL/min). The two diastereomerswere then separated by preparative HPLC (XBridge C18 OBD 30×50 mm,MeCN/H₂O (0.1% formic acid), 75 mL/min). The faster running diastereomerwas isolated as Example 2N (1.8 mg, 3.54 μmol) as the formate salt andthe slower running diastereomer was isolated as Example 2O (2.2 mg, 4.33μmol) as the formate salt.

Example 2N formate salt

LCMS: Rt: 1.00 min (LCMS Method 3) MS m/z 437.3 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.50 (s, 1H), 8.39 (s, 1H), 7.33 (dd, J=7.0,2.1 Hz, 1H), 7.25-7.12 (m, 3H), 4.23-4.00 (m, 5H), 3.69-3.59 (m, 2H),3.54 (t, J=8.6 Hz, 1H), 3.26-3.14 (m, 1H), 3.06 (m, 2H), 2.87 (m 1H),2.55 (dd, J=13.3, 7.9 Hz, 1H), 2.29-1.80 (m, 13H), 1.72 (m, 2H),1.55-1.43 (m, 2H).

Example 2O Formate Salt

LCMS: Rt: 1.13 min (LCMS Method 3) MS m/z 437.3 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.47 (d, J=4.7 Hz, 1H), 8.39 (s, 1H),7.31-7.25 (m, 1H), 7.24-7.20 (m, 1H), 7.17 (td, J=5.2, 4.5, 3.2 Hz, 2H),4.21-4.01 (m, 4H), 3.64 (m, 3H), 3.57-3.45 (m, 1H), 3.24-3.11 (m, 1H),3.04 (d, J=14.5 Hz, 2H), 2.82 (m, 1H), 2.55 (dd, J=13.3, 7.8 Hz, 1H),2.19 (m, 2H), 2.12-1.91 (m, 8H), 1.90-1.72 (m, 3H), 1.63 (m, 2H),1.52-1.38 (m, 2H).

Example 3A:(R)-2-(6-(4-(2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole

(R)-6-(4-(2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 4N, 70 mg, 0.20 mmol), 2-bromo-1,3,4-thiadiazole (34 mg,0.20 mmol) and potassium phosphate (43 mg, 0.20 mmol) were suspended ina mixture of 2% aqueous TPGS-750-M (0.37 mL) and THE (0.04 mL). Thereaction was stirred at RT for 16 hours and then the solution wasextracted with DCM, and the combined organic layers were concentrated.The residue was purified by FCC (0-7% MeOH/DCM) and further bypreparative HPLC (XBridge 30×50 mm 25-50% MeCN/H₂O (5 mM NH₄OH)) toafford the title compound (21 mg, 0.048 mmol).

LCMS: Rt: 2.09 min (LCMS Method 4) MS m/z 427.3 [M+H]⁺.

¹H NMR (DMSO-d₆) δ 8.78 (s, 1H), 7.21 (dd, J=7.8, 1.5 Hz, 1H), 7.16-7.04(m, 1H), 6.98-6.87 (m, 1H), 6.53 (d, J=7.8 Hz, 1H), 5.75 (s, 1H), 5.27(q, J=5.5 Hz, 1H), 4.93 (t, J=6.8 Hz, 2H), 4.53 (dd, J=7.6, 5.1 Hz, 2H),4.03-3.84 (m, 4H), 3.29 (br s, 1H), 3.04 (br s, 2H), 2.91 (t, J=11.7 Hz,1H), 2.21-2.12 (m, 1H), 2.12-1.81 (m, 4H), 1.80-1.69 (m, 3H), 1.69-1.43(m, 3H).

Example 3B:2-((R)-6-(4-(2-(((R)-1,4-dioxan-2-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole

(R)-6-(4-(2-(((R)-1,4-dioxan-2-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 40, 142 mg, 0.367 mmol)), 2-bromo-1,3,4-thiadiazole (61mg, 0.37 mmol) and potassium phosphate (78 mg, 0.37 mmol) were suspendedin a mixture of 2% aqueous TPGS-750-M (0.66 mL) and THF (0.07 mL). Thereaction was stirred at RT for 16 hours and then it was extracted withDCM, and the combined organic layers were concentrated. The residue waspurified by FCC (0-7% MeOH/DCM) and further by preparative HPLC (XBridge30×50 mm 25-50% MeCN/H₂O (5 mM NH₄OH)) to afford the title compound (52mg, 0.11 mmol).

LCMS: Rt: 2.18 min (LCMS Method 4) MS m/z 471.2 [M+H]⁺.

¹H NMR (DMSO-d₆) δ 8.77 (s, 1H), 7.19-7.11 (m, 2H), 6.95-6.85 (m, 2H),4.04-3.82 (m, 8H), 3.80-3.75 (m, 1H), 3.72-3.59 (m, 2H), 3.54-3.44 (m,2H), 3.10-3.00 (m, 2H), 2.88-2.78 (m, 1H), 2.71-2.57 (m, 1H), 2.16 (dd,J=12.7, 6.8 Hz, 1H), 2.09-1.80 (m, 5H), 1.79-1.66 (m, 3H), 1.66-1.43 (m,3H).

Example 3C:2-((R)-6-(4-(2-(((S)-1,4-dioxan-2-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole

(R)-6-(4-(2-(((S)-1,4-dioxan-2-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 4P, 164 mg, 0.424 mmol), 2-bromo-1,3,4-thiadiazole (70 mg,0.42 mmol) and potassium phosphate (90 mg, 0.42 mmol) were suspended ina mixture of 2% aqueous TPGS-750-M (0.76 mL) and THF (0.09 mL). Thereaction was stirred at RT for 16 hours and it was then extracted withDCM, and the combined organic layers were concentrated. The residue waspurified by FCC (0-7% MeOH/DCM) and further by preparative HPLC (XBridge30×50 mm 35-60% MeCN/H₂O (5 mM NH₄OH)) to afford the title compound (74mg, 0.15 mmol).

LCMS: Rt: 2.18 min (LCMS Method 4) MS m/z 471.7 [M+H]⁺.

¹H NMR (DMSO-d₆) δ 8.78 (s, 1H), 7.19-7.10 (m, 2H), 6.95-6.87 (m, 2H),4.03-3.82 (m, 8H), 3.81-3.74 (m, 1H), 3.71-3.60 (m, 2H), 3.55-3.44 (m,2H), 3.04 (br s, 2H), 2.90-2.78 (m, 1H), 2.66-2.57 (m, 1H), 2.16 (dd,J=12.2, 7.3 Hz, 1H), 2.08-1.80 (m, 5H), 1.80-1.67 (m, 3H), 1.66-1.43 (m,3H).

Example 3D:(R)-2-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole

(R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 4Q, 127 mg, 0.423 mmol), 2-bromo-1,3,4-thiadiazole (70 mg,0.42 mmol) and potassium phosphate (90 mg, 0.42 mmol) were suspended ina mixture of 2% aqueous TPGS-750-M (0.76 mL) and THE (0.09 mL). Thereaction was stirred at RT for 16 hours and then extracted with DCM andthe combined organic layers were concentrated. The residue was purifiedby FCC (0-10% MeOH/DCM) and further by preparative HPLC (XBridge 30×50mm 35-60% MeCN/H₂O (5 mM NH₄OH)) to afford the title compound (60 mg,0.15 mmol).

LCMS: Rt: 1.33 min (LCMS Method 3) MS m/z 385.4 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) δ 8.78 (s, 1H), 7.22-7.12 (m, 2H),7.00-6.85-7.00 (m, 2H), 4.02-3.85 (m, 4H), 3.77 (s, 3H), 3.29 (s, 1H),3.00 (br s, 2H), 2.91-2.81 (m, 1H), 2.23-2.10 (m, 1H), 2.05-1.79 (m,5H), 1.78-1.42 (m, 6H).

Example 3E:(R)-2-(6-(4-(3-fluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole

(R)-6-(4-(3-fluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 4J, 50 mg, 0.14 mmol), 2-bromo-1,3,4-thiadiazole (70 mg,0.42 mmol) and potassium phosphate (90 mg, 0.42 mmol) were suspended ina mixture of 2% aqueous TPGS-750-M (0.76 mL) and THE (0.085 mL). Thereaction was stirred at RT for 16 hours and then extracted with ethylacetate, and the combined organic layers were washed with water, driedwith MgSO₄, filtered and concentrated. The residue was purified bypreparative HPLC (XBridge 30×50 mm 25-50% MeCN/H₂O (5 mM NH₄OH)) toafford the title compound (16 mg, 0.034 mmol).

LCMS: Rt: 2.10 min (LCMS Method 4) MS m/z 445.2 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.64 (s, 1H), 7.08-6.89 (m, 3H), 5.11 (m, 1H),4.92 (dd, J=7.5, 6.2 Hz, 2H), 4.84-4.78 (m, 2H), 4.18-3.90 (m, 4H), 3.16(m, 2H), 3.01 (m, 1H), 2.73 (m, 1H), 2.31 (dd, J=12.9, 7.2 Hz, 1H),2.22-1.91 (m, 5H), 1.89-1.68 (m, 5H), 1.66-1.52 (m, 1H).

Example 3F:(R)-2-(6-(4-(2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole

(R)-6-(4-(2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 4E, 89 mg, 0.26 mmol), 2-bromo-1,3,4-thiadiazole (43 mg,0.26 mmol) and potassium phosphate (55 mg, 0.26 mmol) were suspended ina mixture of 2% aqueous TPGS-750-M (0.46 mL) and THE (0.05 mL). Thereaction was stirred at RT for 16 hours and then extracted with EtOAcand the combined organic layers were washed with water, dried withMgSO₄, filtered and concentrated. The residue was purified bypreparative HPLC (XBridge 30×50 mm 35-60% MeCN/H₂O (5 mM NH₄OH)) toafford the title compound (46 mg, 0.11 mmol).

LCMS: Rt: 2.25 min (LCMS Method 4) MS m/z 429.2 [M+H]⁺.

¹H NMR (DMSO-d₆) δ 8.78 (s, 1H), 7.19-7.11 (m, 2H), 6.96-6.87 (m, 2H),4.11-4.06 (m, 2H), 3.99-3.87 (m, 4H), 3.67 (dd, J=5.4, 3.9 Hz, 2H), 3.33(s, 3H), 3.10-2.96 (m, 2H), 2.93-2.82 (m, 1H), 2.65-2.54 (m, 1H),2.21-2.11 (m, 1H), 2.03-1.80 (m, 5H), 1.79-1.67 (m, 3H), 1.65-1.45 (m,3H).

Example 3G:(R)-1-(2-(1-(2-(1,3,4-thiadiazol-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)-2-methylpropan-2-ol

(R)-1-(2-(1-(2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)-2-methylpropan-2-ol(Intermediate 4C, 75 mg, 0.21 mmol), 2-bromo-1,3,4-thiadiazole (35 mg,0.21 mmol) and potassium phosphate (44 mg, 0.21 mmol) were suspended ina mixture of 2% aqueous TPGS-750-M (0.38 mL) and THE (0.04 mL). Thereaction was stirred at RT for 16 hours and then extracted with EtOAcand the combined organic layers were washed with water, dried withMgSO₄, filtered and concentrated. The residue was purified bypreparative HPLC (XBridge 30×50 mm 25-50_(%)MeCN/H₂O (5 mM NH₄OH)) toafford the title compound (25 mg, 0.055 mmol).

LCMS: Rt: 2.13 min (LCMS Method 4) MS m/z 443.3 [M+H]⁺.

¹H NMR (DMSO-d₆) δ 8.77 (s, 1H), 7.19-7.09 (m, 2H), 6.92-6.83 (m, 2H),4.63 (s, 1H), 4.01-3.83 (m, 4H), 3.68 (s, 2H), 3.09-2.98 (m, 2H),2.94-2.84 (m, 1H), 2.66-2.54 (m, 1H), 2.14 (dd, J=13.0, 7.1 Hz, 1H),2.04-1.79 (m, 5H), 1.78-1.67 (m, 3H), 1.65-1.40 (m, 3H), 1.23 (s, 6H).

Example 3H:(R)-4-(2-(1-(2-(1,3,4-thiadiazol-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)-2-methylbutan-2-ol

(R)-4-(2-(1-(2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)-2-methylbutan-2-ol(Intermediate 4R, 550 mg, 1.48 mmol), 2-bromo-1,3,4-thiadiazole (244 mg,1.48 mmol) and potassium phosphate (313 mg, 1.48 mmol) were suspended ina mixture of 2% aqueous TPGS-750-M (2.7 mL) and THF (0.3 mL). Thereaction was stirred at RT for 16 hours and then extracted with DCM andthe combined organic layers were washed with water, dried with MgSO₄,filtered and concentrated. The residue was purified by FCC (0-7%MeOH/DCM) and further by preparative HPLC (XBridge 30×50 mm 35-60%MeCN/H₂O (5 mM NH₄OH)) to afford the title compound (155 mg, 0.333mmol).

LCMS: Rt: 2.23 min (LCMS Method 4) MS m/z 457.3 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) δ 8.77 (s, 1H), 7.20-7.08 (m, 2H), 6.94 (d,J=7.8 Hz, 1H), 6.87 (t, J=7.3 Hz, 1H), 4.36 (s, 1H), 4.06 (t, J=6.8 Hz,2H), 4.02-3.84 (m, 4H), 3.00 (d, J=10.8 Hz, 2H), 2.88-2.82 (m, 1H), 2.59(s, 1H), 2.14 (dd, J=12.8, 7.0 Hz, 1H), 2.02-1.77 (m, 7H), 1.77-1.40 (m,6H), 1.18 (s, 6H).

Example 31:(R)-5-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)isothiazole

(R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octane (Example4Q, 90 mg, 0.30 mmol) and 5-bromoisothiazole (59 mg, 0.36 mmol) weredissolved in toluene (3 mL) and purged with nitrogen. Sodiumtert-butoxide (86 mg, 0.90 mmol), Pd₂(dba)₃ (27 mg, 0.030 mmol) andracemic-BINAP (37 mg, 0.060 mmol) were added and the reaction was heatedin the microwave at 120° C. for 1 hour and then filtered, andconcentrated under reduced pressure. The residue was purified by FCC(0-10% MeOH(10% NH₄OH)/DCM) to afford the title compound (43 mg, 0.11mmol).

LCMS: Rt: 2.80 min (LCMS Method 4) MS m/z 384.4 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.97 (d, J=2.4 Hz, 1H), 7.23-7.11 (m, 2H),6.97-6.84 (m, 2H), 6.12 (d, J=2.0 Hz, 1H), 3.97-3.82 (m, 4H), 3.81 (s,3H), 3.22-3.10 (m, 2H), 2.98 (m, 1H), 2.78-2.65 (m, 1H), 2.29 (dd,J=12.9, 7.2 Hz, 1H), 2.22-2.10 (m, 2H), 2.10-1.92 (m, 3H), 1.86-1.73 (m,5H), 1.67-1.53 (m, 1H).

Example 3J:(R)-5-(6-(4-(2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,2,4-thiadiazole

(R)-6-(4-(2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 4E, 78 mg, 0.23 mmol) was dissolved in IPA (2 mL) andDIPEA (145 mg, 1.13 mmol) was added followed by5-bromo-1,2,4-thiadiazole (56 mg, 0.34 mmol). The reaction was stirredat RT for 1 hour and then purified by preparative HPLC (XBridge 30×50 mm35-60% MeCN/H₂O (5 mM NH₄OH)) to afford the title compound (70 mg, 0.16mmol).

LCMS: Rt: 2.39 min (LCMS Method 4) MS m/z 429.5 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.94 (s, 1H), 7.27-7.09 (m, 2H), 6.93 (t,J=7.6 Hz, 2H), 4.18-4.12 (m, 3H), 4.06 (m, 3H), 3.82-3.76 (m, 2H), 3.46(s, 3H), 3.21 (s, 2H), 3.09 (m, 1H), 2.87-2.73 (m, 1H), 2.35 (m, 1H),2.23 (m, 2H), 2.15-1.96 (m, 3H), 1.95-1.85 (m, 3H), 1.83-1.59 (m, 3H).

Example 3K:(R)-1-(2-(1-(2-(1,2,4-thiadiazol-5-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)-2-methylpropan-2-ol

(R)-1-(2-(1-(2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)-2-methylpropan-2-ol(Intermediate 4C, 75 mg, 0.21 mmol) was dissolved in THE (2 mL) and5-bromo-1,2,4-thiadiazole (52 mg, 0.31 mmol) was added as a solution inTHE (0.5 mL). The reaction was stirred at RT for 4 hours, thenconcentrated and purified by FCC (0-10% MeOH (10% NH₄OH)/DCM) to affordthe title compound (38 mg, 0.084 mmol).

LCMS: Rt: 2.26 min (LCMS Method 4) MS m/z 443.4 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.92 (s, 1H), 7.25-7.07 (m, 2H), 6.90 (t,J=7.4 Hz, 2H), 5.49 (s, 1H), 4.19-3.95 (m, 4H), 3.77 (s, 2H), 3.26-3.04(m, 3H), 2.76 (s, 1H), 2.33 (dd, J=13.0, 7.3 Hz, 1H), 2.20 (s, 2H),2.14-1.95 (m, 3H), 1.95-1.82 (m, 3H), 1.75 (m, 2H), 1.68-1.53 (m, 1H),1.35 (s, 6H).

Example 3L:(R)-4-(2-(1-(2-(1,2,4-thiadiazol-5-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)-2-methylbutan-2-ol

(R)-4-(2-(1-(2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)-2-methylbutan-2-ol(Intermediate 4R, 80 mg, 0.21 mmol) was dissolved in IPA (3 mL) and5-bromo-1,2,4-thiadiazole (53 mg, 0.32 mmol) was added as a solution inIPA (0.5 mL). The reaction was stirred at RT for 16 h, and thenconcentrated and purified by FCC (0-10% MeOH(10% NH₄OH)/DCM) to affordthe title compound (45 mg, 0.094 mmol).

LCMS: Rt: 2.37 min (LCMS Method 4) MS m/z 457.5 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.92 (s, 1H), 7.15 (m, 2H), 6.96-6.84 (m, 2H),5.49 (s, 1H), 4.17-4.09 (m, 3H), 4.03 (m, 3H), 3.15 (d, J=11.9 Hz, 2H),3.01 (m, 1H), 2.73 (d, J=9.0 Hz, 1H), 2.32 (dd, J=12.9, 7.3 Hz, 1H),2.22-2.09 (m, 2H), 2.09-1.96 (m, 5H), 1.90-1.55 (m, 6H), 1.29 (s, 6H).

Example 3M:(R)-5-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-3-methyl-1,2,4-thiadiazole

Step 1:(R)-3-bromo-5-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,2,4-thiadiazole

(R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 4Q, 71 mg, 0.236 mmol) was added to a vial followed by asolution of 3-bromo-5-chloro-1,2,4-thiadiazole (71 mg, 0.354 mmol) indioxane (2.4 mL). A white solid formed and the reaction was sonicated tobreak up clumps of solid on the bottom of the vial and this was placedunder nitrogen and stirred for 16 hours. The reaction was left insolution for 7 days and then it was concentrated and purified by FCC(0-15% MeOH (10% NH₄OH)/DCM) to yield the product as a colorless oil.

LCMS: Rt: 2.89 mins (LCMS Method 4) MS m/z 463.3 [M+H]⁺.

Step 2:(R)-5-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-3-methyl-1,2,4-thiadiazole

(R)-3-bromo-5-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,2,4-thiadiazole(35 mg, 0.076 mmol) was dissolved in THE (0.5 mL) and under nitrogen wasadded XPhos Pd G2 (15 mg, 0.019 mmol) and dimethylzinc (2.0 M intoluene, 0.076 mL, 0.151 mmol) was added dropwise via syringe. Thereaction was stirred for 16 hours at RT and then it was quenched withwater (1 mL) and extracted with EtOAc (2×25 mL) and 3:1 DCM:iPrOH (2×25mL). The combined organic layers were dried over magnesium sulfate,filtered and concentrated. The residue was purified by preparative HPLC(XBridge 30×50 mm, 35-60% MeCN/H₂O (5 mM NH₄OH) to yield the titlecompound as an off white solid.

LCMS: Rt: 2.53 mins (LCMS Method 4) MS m/z 399.4 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.22-7.11 (m, 2H), 6.96-6.86 (m, 2H),4.15-3.94 (m, 4H), 3.81 (s, 3H), 3.28-3.17 (m, 2H), 3.11-2.85 (m, 2H),2.45-2.25 (m, 6H), 2.16-1.73 (m, 8H), 1.73-1.57 (m, 1H).

Example 3N:(R)-1-(5-fluoro-2-(1-(2-(4-methyloxazol-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)-2-methylpropan-2-ol

Into a vial was added(R)-1-(2-(1-(2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)-5-fluorophenoxy)-2-methylpropan-2-ol(Intermediate 4T, 100 mg, 0.266 mmol) followed by a solution of2-bromo-4-methyloxazole (51.6 mg, 0.319 mmol) in dioxane (3 mL) and thiswas placed under nitrogen. Pd₂(dba)₃ (15.27 mg, 0.027 mmol), xantphos(18.44 mg, 0.032 mmol) and NaOtBu (51.0 mg, 0.531 mmol) were added andthe reaction was stirred at 75° C. for 2.5 hr. The reaction was cooledto room temperature, filtered, and rinsed through with MeCN and EtOAc.The filtrate was concentrated and the residue was purified by FCC (0-10%MeOH(1% NH₄OH)/DCM) to yield the title compound (24 mg, 0.047 mmol) as alight yellow glassy solid.

LCMS: Rt: 2.54 min (LCMS Method 3) MS m/z 458.3 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.29-6.99 (m, 2H), 6.81-6.48 (m, 2H),4.09-3.83 (m, 4H), 3.76 (s, 2H), 3.22-3.09 (m, 2H), 3.02 (m, 1H),2.81-2.60 (m, 1H), 2.33-2.08 (m, 3H), 2.07-1.65 (m, 11H), 1.65-1.52 (m,1H), 1.34 (s, 6H).

Example 30:(R)-2-methyl-1-(2-(1-(2-(4-methyloxazol-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)propan-2-ol

Into a vial was added(R)-1-(2-(1-(2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)-2-methylpropan-2-ol(Intermediate 4C, 90 mg, 0.251 mmol) followed by a solution of2-bromo-4-methyloxazole (48.8 mg, 0.301 mmol) in dioxane (3 mL) and thiswas placed under nitrogen. Pd₂(dba)₃ (14.43 mg, 0.025 mmol), xantphos(17.43 mg, 0.030 mmol) and NaOtBu (48.3 mg, 0.502 mmol) were added andthis was stirred at 75° C. for 16 hours. The reaction was then cooled toroom temperature, filtered, and rinsed through with MeCN and EtOAc. Thefiltrate was concentrated and the residue was purified by FCC (0-10%MeOH(1% NH₄OH)/DCM) to yield the title compound (15 mg, 0.031 mmol).

LCMS: Rt: 2.40 min (LCMS Method 3) MS m/z 440.5 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.28-7.01 (m, 3H), 6.90 (t, J=7.3 Hz, 2H),4.08-3.83 (m, 4H), 3.77 (s, 2H), 3.23-3.09 (m, 3H), 2.74 (s, 1H),2.42-2.08 (m, 3H), 2.07-1.69 (m, 11H), 1.66-1.47 (m, 1H), 1.35 (s, 6H).

Example 4A:(R)-3-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,2,4-oxadiazole

Step 1: 3-bromo-5-(trichloromethyl)-1,2,4-oxadiazole

Sodium bicarbonate (2.65 g, 31.6 mmol) and 2,2,2-trichloroacetonitrile(1.98 mL, 19.7 mmol) were suspended in toluene (3.3 mL), and incubatedat 80° C. under nitrogen. Next, a solution of dibromoformaldoxime (2.0g, 9.9 mmol) in toluene (3.3 mL) was added dropwise over 25 minutes, andthe reaction was incubated at 80° C. for 16 h, then cooled and dilutedwith water (25 mL), and extracted with EtOAc (2×50 mL). The combinedorganic layers were dried with MgSO₄, filtered and concentrated. Theresidue was then purified by FCC (0-40% EtOAc/heptanes) to afford thetitle intermediate (1.38 g, 5.18 mmol) as a pale yellow oil. ¹³C NMR(101 MHz, MeOD) δ 176.66, 151.34, 83.60.

Step 2:(R)-3-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-5-(trichloromethyl)-1,2,4-oxadiazole

(R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 4Q, 0.16 g, 0.53 mmol),3-bromo-5-(trichloromethyl)-1,2,4-oxadiazole (0.15g, 0.16 mmol) andpotassium phosphate (0.17 g, 0.80 mmol) were suspended in a mixture of2% (wt) aqueous TPGS-750-M (2.4 mL) and THE (0.27 mL). The reaction wasstirred for 20 minutes and then diluted with water (25 mL) and brine (25mL) and extracted with EtOAc (3×50 mL). The combined organic layers werewashed with brine (1×10 mL), dried with MgSO₄, filtered andconcentrated. The residue was purified by FCC (0-10% MeOH(10%NH₄OH)/DCM) to afford the title intermediate (68 mg, 0.14 mmol).

LCMS: Rt: 0.91 min (LCMS Method 1) MS m/z 485.2 [M+H]⁺.

Step 3:(R)-3-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,2,4-oxadiazole

(R)-3-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-5-(trichloromethyl)-1,2,4-oxadiazole(68 mg, 0.14 mmol) was dissolved in a mixture of THE (0.7 mL) and MeOH(0.7 mL) under nitrogen, and sodium borohydride (0.016 g, 0.420 mmol)was added. The reaction was stirred for 16 hr at RT, then diluted withwater (10 mL) and brine (10 mL) and extracted with EtOAc (3×25 mL). Thecombined organic layers were washed with water (1×10 mL), dried withMgSO₄, filtered and concentrated. The residue was purified by FCC (0-10%MeOH (10% NH₄OH)/DCM) and further by preparative HPLC (XBridge 30×50 mm10-30% MeCN/H₂O (0.1% formic acid)). The residue was concentrated,diluted with a 1N solution of NaOH until pH ˜13, and then extracted withethyl acetate (3×25 mL). The combined organic extracts were washed witha 0.1 N solution of NaOH (3×10 mL), dried with MgSO₄, filtered andconcentrated. The residue was purified twice by preparative HPLC(XBridge Peptide BEH C18 5 μm 19×150 mm 50-65% MeCN/H₂O (10 mM NH₄OH))to afford the title compound (8.0 mg, 0.020 mmol).

LCMS: Rt: 2.46 min (LCMS Method 4) MS m/z 369.4 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.77 (s, 1H), 7.22-7.10 (m, 2H), 6.97-6.81 (m,2H), 4.03-3.85 (m, 4H), 3.81 (s, 3H), 3.22-3.08 (m, 2H), 3.05-2.90 (m,1H), 2.79-2.63 (m, 1H), 2.28 (dd, J=12.8, 7.3 Hz, 1H), 2.22-2.10 (m,2H), 2.10-1.87 (m, 3H), 1.86-1.68 (m, 5H), 1.67-1.49 (m, 1H).

Example 5A:(R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octaneformate salt

Into a vial was added(R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 4Q, 22.00 mg, 0.073 mmol) followed by a solution of5-bromopyrimidine (17.46 mg, 0.110 mmol) in toluene (1.0 mL) and thiswas placed under nitrogen. Pd₂(dba)₃ (6.71 mg, 7.32 μmol), rac-BINAP(4.56 mg, 7.32 μmol) and NaOtBu (10.56 mg, 0.110 mmol) were added andthis was stirred at 110° C. for 4 hours. The reaction mixture was thencooled to RT, filtered and the filtrate was concentrated. The residuewas then purified by FCC (0-10% MeOH (1% NH₄OH)/DCM) and further bypreparative HPLC (XBridge 30×50 mm 10-30% MeCN/H₂O (0.1% formic acid))to yield the title compound (15 mg, 0.038 mmol) as a formate salt.

LCMS: Rt: 0.59 min (LCMS Method 1) MS m/z 380.5 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 8.62 (s, 1H), 8.49 (s, 1H), 7.92 (s, 2H), 7.19(m, 2H), 6.92 (td, J=7.5, 1.1 Hz, 1H), 6.86-6.81 (m, 1H), 3.97 (d, J=7.3Hz, 1H), 3.88 (d, J=7.3 Hz, 1H), 3.80 (s, 3H), 3.79 (s, 2H), 3.55 (t,J=11.9 Hz, 2H), 3.20-3.02 (m, 2H), 2.66-2.48 (m, 2H), 2.41 (dd, J=13.4,9.0 Hz, 1H), 2.32 (dd, J=13.3, 8.1 Hz, 1H), 2.25-2.10 (m, 4H), 2.07 (m,1H), 1.99-1.85 (m, 3H).

Example 5B:(R)-2-methyl-1-(2-(1-(2-(pyrimidin-5-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)propan-2-olformate salt

Into a vial was added(R)-1-(2-(1-(2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)-2-methylpropan-2-ol(Intermediate 4C, 60 mg, 0.167 mmol) and 5-bromopyrimidine (39.9 mg,0.251 mmol) followed by a solution of cesium carbonate (136 mg, 0.418mmol) in dioxane (2.0 mL) and this was placed under nitrogen. xantphos(19.37 mg, 0.033 mmol), Pd₂(dba)₃ (9.62 mg, 0.017 mmol) and cesiumcarbonate (136 mg, 0.418 mmol) were added and this was stirred at 110°C. for 4 hours. The reaction mixture was then cooled to RT and filteredand the filtrate was concentrated. The residue was then purified by FCC(0-10% MeOH (1% NH₄OH)/DCM) and further by preparative HPLC (XBridge30×50 mm 10-30% MeCN/H₂O (0.1% formic acid)) to yield the title compound(41 mg, 0.09 mmol) as a formate salt.

LCMS: Rt: 0.66 min (LCMS Method 1) MS m/z 437.2 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 8.63 (s, 1H), 8.53 (s, 1H), 7.93 (s, 2H), 7.19(ddd, J=9.8, 7.6, 2.1 Hz, 2H), 6.93 (t, J=7.5 Hz, 1H), 6.86 (d, J=8.2Hz, 1H), 3.97 (d, J=7.3 Hz, 1H), 3.89 (d, J=7.3 Hz, 1H), 3.80 (s, 4H),3.53 (t, J=11.3 Hz, 2H), 3.16 (p, J=8.5 Hz, 1H), 2.98-2.92 (m, 1H),2.60-2.45 (m, 2H), 2.45-2.26 (m, J=9.6, 8.1 Hz, 4H), 2.20-2.05 (m, 3H),1.96-1.91 (m, 3H), 1.36 (s, 6H).

Example 5C:(R)-2-methyl-1-(2-(1-(2-(4-methylpyrimidin-5-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)propan-2-olformate salt

Into a vial was added(R)-1-(2-(1-(2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)-2-methylpropan-2-ol(Intermediate 4C, 60 mg, 0.167 mmol) and 5-bromo-4-methylpyrimidine(43.4 mg, 0.251 mmol) followed by a solution of cesium carbonate (136mg, 0.418 mmol) in dioxane (2.0 mL) and this was placed under nitrogen.xantphos (19.37 mg, 0.033 mmol), Pd₂(dba)₃ (9.62 mg, 0.017 mmol) andcesium carbonate (136 mg, 0.418 mmol) were added and this was stirred at110° C. for 4 hours. The reaction was cooled to RT and filtered and thefiltrate was concentrated. The residue was then purified by HPLC(XBridge C18 OBD 30×50 mm 15-40% MeCN/H₂O (0.1% formic Acid) 75 mL/min)to yield the title compound (46 mg, 0.099 mmol) as a brown oil and aformate salt.

LCMS: Rt: 0.64 min (LCMS Method 1) MS m/z 451.7 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 8.57 (s, 1H), 8.36 (s, 1H) 7.78 (s, 1H),7.22-7.15 (m, 2H), 6.92 (t, J=7.5 Hz, 1H), 6.85 (d, J=8.1 Hz, 1H), 4.03(d, J=7.3 Hz, 1H), 3.92 (d, J=7.2 Hz, 1H), 3.79 (s, 4H), 3.64 (q, J=9.3,8.8 Hz, 2H), 3.26 (t, J=8.5 Hz, 1H), 2.98 (t, J=11.9 Hz, 1H), 2.55 (m,5H), 2.37 (s, 3H), 2.36-2.04 (m, 4H), 2.01-1.85 (m, 3H), 1.35 (s, 6H).

Example 5D:(R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(6-methylpyridin-3-yl)-2-azaspiro[3.4]octaneformate salt

Into a vial was added(R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 4Q, 45 mg, 0.150 mmol) followed by a solution of5-bromo-2-methylpyridine (38.6 mg, 0.225 mmol) in toluene (1.5 mL) andthis was placed under nitrogen. Pd₂(dba)₃ (13.72 mg, 0.015 mmol),rac-BINAP (9.33 mg, 0.015 mmol) and NaOtBu (21.59 mg, 0.225 mmol) wereadded and this was stirred at 110° C. for 4 hours. The reaction wascooled to RT, filtered and the filtrate was concentrated. The residuewas then purified by FCC (0-10% MeOH (1% NH₄OH)/DCM) and further bypreparative HPLC (XBridge C18 OBD 30×50 mm 5-20% MeCN/H₂O (0.1% formicAcid) 75 mL/min) to yield the title compound (17 mg, 0.041 mmol).

LCMS: Rt: 0.42 min (LCMS Method 1) MS m/z 392.4 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 8.46 (s, 1H), 7.76 (d, J=2.9 Hz, 1H), 7.21 (t,J=7.5 Hz, 2H), 7.01 (d, J=8.3 Hz, 1H), 6.94 (t, J=7.4 Hz, 1H), 6.85 (d,J=8.2 Hz, 1H), 6.74 (dd, J=8.3, 2.9 Hz, 1H), 3.91 (d, J=7.3 Hz, 1H),3.82 (d, J=3.7 Hz, 4H), 3.70 (d, J=27.2 Hz, 4H), 3.47 (s, 1H), 3.30-3.23(m, 1H), 3.13 (tt, J=12.2, 3.6 Hz, 1H), 2.70 (t, J=12.5 Hz, 2H), 2.46(s, 4H), 2.40-2.03 (m, 6H), 2.03-1.85 (m, 3H).

Example 5E:(R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(2-methylpyrimidin-5-yl)-2-azaspiro[3.4]octane

Into a vial was added(R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 4Q, 25 mg, 0.083 mmol) followed by a solution of5-bromo-2-methylpyrimidine (21.59 mg, 0.125 mmol) in toluene (1.0 mL)and this was placed under nitrogen. Pd₂(dba)₃ (7.62 mg, 8.32 μmol),rac-BINAP (5.18 mg, 8.32 μmol) and NaOtBu (12.00 mg, 0.125 mmol) wereadded and this was stirred at 110° C. for 4 hours. The reaction was thencooled to RT and filtered and the filtrate was concentrated. The residuewas then purified by FCC (0-10% MeOH (1% NH₄OH)/DCM) to yield the titlecompound (20 mg, 0.048 mmol).

LCMS: Rt: 0.66 min (LCMS Method 1) MS m/z 393.4 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 7.85 (s, 2H), 7.22-7.15 (m, 2H), 6.95-6.80 (m,2H), 3.93 (d, J=7.1 Hz, 1H), 3.82 (d, J=16.8 Hz, 4H), 3.75 (s, 2H), 3.57(t, J=12.3 Hz, 2H), 3.21-3.01 (m, 2H), 2.59 (s, 5H), 2.44-2.01 (m, 7H),1.92 (dd, J=13.6, 9.9 Hz, 3H).

Example 5F:(R)-2-(5-fluoropyridin-3-yl)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octane

Into a vial was added(R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 4Q, 150 mg, 0.499 mmol) followed by a solution of3-bromo-5-fluoropyridine (132 mg, 0.749 mmol) in dioxane (2.0 mL) andthis was placed under nitrogen. Pd₂(dba)₃ (29 mg, 0.05 mmol), xantphos(58 mg, 0.10 mmol) and cesium carbonate (407 mg, 1.248 mmol) were addedand this was stirred at 110° C. for 2 hours. The reaction was thencooled to RT and the reaction was filtered and the filtrate wasconcentrated. The residue was then purified by FCC (0-10% MeOH (1%NH₄OH)/DCM) and further by preparative HPLC (XBridge C18 OBD 30×50 mm 5μm column MeCN/H₂Ow/5 mM NH₄OH 75 mL/min) to yield the title compound(54 mg, 0.135 mmol).

LCMS: Rt: 1.22 min (LCMS Method 2) MS m/z 396.6 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 7.81 (d, J=2.4 Hz, 1H), 7.62 (t, J=1.8 Hz,1H), 7.22-7.12 (m, 2H), 6.91 (t, J=7.4 Hz, 1H), 6.83 (d, J=8.3 Hz, 1H),6.37 (m, 1H), 3.85 (d, J=7.2 Hz, 1H), 3.81 (d, J=2.5 Hz, 4H), 3.74 (s,2H), 3.17 (t, J=12.8 Hz, 2H), 2.97 (m, 1H), 2.69 (m, 1H), 2.24 (dd,J=12.9, 7.2 Hz, 1H), 2.18-1.87 (m, 6H), 1.84 (m, 4H), 1.75-1.65 (m, 1H).

Example 5G:(R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(6-methylpyrazin-2-yl)-2-azaspiro[3.4]octane

(R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 4Q, 75 mg, 0.250 mmol) was dissolved in IPA (2 mL) andcooled to 0° C. under nitrogen. Triethylamine (0.08 mL, 0.549 mmol) wasadded, followed by a solution of 2-chloro-6-methylpyrazine (35.3 mg,0.275 mmol) in IPA (0.5 mL) and the reaction was stirred at 0° C. for 10minutes. The reaction was then warmed to 50° C. and stirred for 18hours. The reaction was then cooled to room temperature andconcentrated. The residue was purified via FCC (0-10% MeOH (1%NH₄OH)/DCM) to afford the title compound (10 mg, 0.025 mmol).

LCMS: RT: 2.63 min (LCMS Method 4) MS m/z 393.4 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.66 (s, 1H), 7.57 (s, 1H), 7.16 (td, J=7.5,1.5 Hz, 2H), 6.97-6.83 (m, 2H), 4.08-3.88 (m, 5H), 3.81 (s, 3H), 3.26(s, 1H), 3.21 (s, 1H), 3.01 (s, 1H), 2.35 (s, 3H), 2.33-2.13 (m, 3H),2.11-1.90 (m, 3H), 1.80 (m, 5H), 1.64 (s, 1H).

Example 5H:(R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(pyrazin-2-yl)-2-azaspiro[3.4]octane

(R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 4Q, 70 mg, 0.233 mmol) was dissolved in DMF (2 mL) andcooled to 0° C. under nitrogen. Triethylamine (0.08 mL, 0.513 mmol) wasadded, followed by a solution of 2-chloropyrazine (0.023 mL, 0.256 mmol)in DMF (0.5 mL) and the reaction was stirred at 0° C. for 10 minutes.The reaction was then warmed to 50° C. and stirred for 18 hours. Thereaction was then cooled to room temperature and diluted with saturatedaqueous sodium bicarbonate. The solution was extracted with DCM, and thecombined organic layers were washed with brine, dried over magnesiumsulfate, filtered, and concentrated. The residue was purified via FCC(0-10% MeOH (1% NH₄OH)/DCM) and further by preparative HPLC (XBridge30×50 mm 35-60% MeCN/H₂O (5 mM NH₄OH)) to afford the title compound (8.5mg, 0.022 mmol).

LCMS: RT: 2.42 min (LCMS Method 4) MS m/z 379.4 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.02 (dd, J=2.9, 1.5 Hz, 1H), 7.83 (d, J=1.5Hz, 1H), 7.80 (d, J=2.9 Hz, 1H), 7.19 (t, J=7.7 Hz, 2H), 6.98-6.87 (m,2H), 4.11-3.93 (m, 4H), 3.84 (s, 3H), 3.19 (m, 2H), 3.02 (s, 1H), 2.80(s, 1H), 2.33 (dd, J=13.1, 7.5 Hz, 1H), 2.22 (s, 2H), 2.14-1.94 (m, 3H),1.93-1.73 (m, 5H), 1.68 (d, J=11.3 Hz, 1H).

Example 51:(R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(3-(trifluoromethyl)pyrazin-2-yl)-2-azaspiro[3.4]octane

To a vial containing(R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 4Q, 65 mg, 0.216 mmol) under an atmosphere of nitrogen wasadded a solution of 2-bromo-3-(trifluoromethyl)pyrazine (58.9 mg, 0.260mmol) in dioxane (2.1 mL). Pd(dba)₂ (12.44 mg, 0.022 mmol), xantphos(15.02 mg, 0.026 mmol) and NaOtBu (41.6 mg, 0.433 mmol) were added andthe reaction mixture was stirred at 75° C. for 18 hours. The reactionwas then cooled to room temperature and filtered, rinsing with MeCN andEtOAc. The filtrate was purified via FCC (0-10% MeOH (1% NH₄OH))/DCM) toafford the title compound (38 mg, 0.082 mmol).

LCMS: RT: 3.20 min (LCMS Method 4) MS m/z 447.8 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.28 (d, J=2.5 Hz, 1H), 7.86 (d, J=2.4 Hz,1H), 7.19-7.12 (m, 2H), 6.96-6.83 (m, 2H), 4.20-4.00 (m, 4H), 3.81 (s,3H), 3.23-3.11 (m, 2H), 2.99 (m, 1H), 2.74 (m, 1H), 2.27 (dd, J=12.8,7.3 Hz, 1H), 2.15 (m, 2H), 2.09-1.99 (m, 2H), 1.99-1.88 (m, 1H), 1.79(m, 5H), 1.70-1.56 (m, 1H).

Example 5J:(R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(3-methylpyrazin-2-yl)-2-azaspiro[3.4]octane

(R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 4Q, 65 mg, 0.216 mmol) was dissolved in THE (2 mL) andcooled to 0° C. under an atmosphere of nitrogen. Triethylamine (0.07 mL,0.476 mmol) was added, followed by a solution of2-chloro-3-methylpyrazine (30.6 mg, 0.238 mmol) in THE (0.5 mL). Thereaction was stirred at 0° C. for 10 minutes and then warmed to 50° C.and stirred for 18 hours. The reaction mixture was then cooled to roomtemperature and diluted with saturated aqueous sodium bicarbonate. Thesolution was extracted with DCM, and the combined organic layers werewashed with brine, dried over magnesium sulfate, filtered, andconcentrated. The residue was purified via preparative HPLC (XBridge30×50 mm 45-70% MeCN/H₂O (5 mM NH₄OH)) to afford the title compound (3.5mg, 0.0085 mmol).

LCMS: RT: 2.61 min (LCMS Method 4) MS m/z 393.6 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.93 (d, J=2.9 Hz, 1H), 7.72 (d, J=2.9 Hz,1H), 7.25-7.09 (m, 2H), 7.00-6.85 (m, 2H), 4.26-3.96 (m, 4H), 3.83 (d,J=1.7 Hz, 3H), 3.18 (d, J=14.2 Hz, 2H), 3.10-2.93 (m, 1H), 2.76 (s, 1H),2.45 (s, 3H), 2.30 (dd, J=12.7, 7.2 Hz, 1H), 2.19 (d, J=8.1 Hz, 3H),2.10-1.93 (m, 2H), 1.87-1.76 (m, 5H), 1.71-1.54 (m, 1H).

Example 5K:(R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(pyridin-3-yl)-2-azaspiro[3.4]octane

(R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 4Q, 45 mg, 0.150 mmol) and 3-bromopyridine (22 μL, 0.225mmol) were dissolved in toluene (1.5 mL) under an atmosphere ofnitrogen. Pd₂(dba)₃ (13.72 mg, 0.015 mmol), rac-BINAP (9.33 mg, 0.015mmol), and NaOtBu (21.59 mg, 0.225 mmol) were added and the reactionmixture was stirred at 110° C. for 3 hours. The reaction was then cooledto room temperature and filtered to remove solids, rinsing with EtOAc.The filtrate was concentrated and the residue was purified via FCC(0-10% MeOH (1% NH₄OH)/DCM) to afford the title compound (30 mg, 0.074mmol).

LCMS: RT: 2.65 min (LCMS Method 4) MS m/z 378.5 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.86 (dd, J=4.8, 1.4 Hz, 1H), 7.75 (d, J=2.9Hz, 1H), 7.24-7.12 (m, 3H), 6.93-6.86 (m, 3H), 3.88-3.74 (m, 7H),3.24-3.12 (m, 2H), 2.99 (m, 1H), 2.74 (p, J=8.4 Hz, 1H), 2.28 (dd,J=12.8, 7.3 Hz, 1H), 2.17 (m, 2H), 2.11-1.90 (m, 3H), 1.85-1.73 (m, 5H),1.68-1.56 (m, 1H).

Example 5L:(R)-2-(6-methylpyridin-3-yl)-6-(4-(2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane

(R)-6-(4-(2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 4D, 120 mg, 0.337 mmol) and 5-bromo-2-methylpyridine (87mg, 0.505 mmol) were dissolved in dioxane (3.4 mL) under an atmosphereof nitrogen. Cs₂CO₃ (274 mg, 0.841 mmol), xantphos (39.0 mg, 0.067mmol), and Pd(dba)₂ (19.35 mg, 0.034 mmol) were added and the reactionmixture was stirred at 80° C. for 72 hours. The reaction mixture wascooled to room temperature and filtered to remove solids, rinsing withEtOAc. The filtrate was concentrated and the residue was then purifiedvia FCC (0-10% MeOH(1% NH₄OH))/DCM) to afford the title compound (34 mg,0.072 mmol).

LCMS: RT: 2.64 min (LCMS Method 4) MS m/z 448.5 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.63 (d, J=2.9 Hz, 1H), 7.24-7.04 (m, 3H),6.97-6.82 (m, 3H), 5.05 (m, 1H), 4.01-3.86 (m, 4H), 3.84-3.77 (m, 2H),3.77-3.68 (m, 2H), 3.17 (q, J=10.2 Hz, 2H), 2.98 (m, 1H), 2.73 (q, J=8.4Hz, 1H), 2.39 (s, 3H), 2.31-2.09 (m, 5H), 2.09-1.88 (m, 3H), 1.78 (m,5H), 1.61 (m, 1H).

Example 5M:(R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(4-methyl-1,3,5-triazin-2-yl)-2-azaspiro[3.4]octane

Step 1:(R)-2-(4-chloro-6-methyl-1,3,5-triazin-2-yl)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octane

To a solution of(R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 4Q, 100 mg, 0.333 mmol) in THF (3 mL) under nitrogen at−78° C. was added triethylamine (0.10 mL, 0.732 mmol) followed by asolution of 2,4-dichloro-6-methyl-1,3,5-triazine (60.0 mg, 0.366 mmol)in THE (0.5 mL). The reaction mixture was stirred at −78° C. for 10 min,then warmed to room temperature over 10 min. The mixture was dilutedwith saturated aqueous sodium bicarbonate and extracted with DCM. Thecombined organic extracts were washed with brine, dried over magnesiumsulfate, filtered, and concentrated to afford the title compound (142mg, 0.333 mmol) as a pale yellow solid that was taken into the next stepwithout further purification.

LCMS: RT: 1.16 min (LCMS Method 2) MS m/z 428.2 [M+H]⁺.

Step 2:(R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(4-methyl-1,3,5-triazin-2-yl)-2-azaspiro[3.4]octane

(R)-2-(4-chloro-6-methyl-1,3,5-triazin-2-yl)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(140 mg, 0.327 mmol) was dissolved in MeOH (15 mL) and subjected to theH-Cube™ with a 10% Pd/C catalyst cartridge for 1 hour at 35° C. and 13psi H₂. The resulting solution was concentrated and purified via FCC(0-10% MeOH (1% NH₄OH))/DCM) to afford the title compound (22 mg, 0.055mmol).

LCMS: RT: 2.28 min (LCMS Method 4) MS m/z 394.8 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.37 (s, 1H), 7.17 (t, J=7.6 Hz, 2H), 6.91(td, J=7.8, 6.5 Hz, 2H), 4.14 (d, J=9.6 Hz, 1H), 4.11-3.96 (m, 3H), 3.83(s, 3H), 3.17 (d, J=10.2 Hz, 2H), 3.00 (m, 1H), 2.76 (d, J=9.4 Hz, 1H),2.38 (s, 3H), 2.29 (dd, J=13.0, 7.3 Hz, 1H), 2.20 (d, J=17.2 Hz, 2H),2.11-1.91 (m, 3H), 1.91-1.71 (m, 5H), 1.71-1.58 (m, 1H).

Example 5N:(R)-2-(6-chloropyridazin-3-yl)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octane

To a solution of(R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 4Q, 75 mg, 0.250 mmol) in isopropanol (2 mL) undernitrogen at 0° C. was added triethylamine (0.08 mL, 0.549 mmol) followedby a solution of 3,6-dichloropyridazine (40.9 mg, 0.275 mmol) inisopropanol (0.5 mL). The reaction mixture was stirred at 0° C. for 10minutes then heated to 50° C. and stirred for 18 hr. The reactionmixture was then diluted with saturated sodium bicarbonate and extractedwith DCM. The combined organic extracts were washed with brine, driedover magnesium sulfate, filtered and concentrated. The crude product waspurified via preparative HPLC (XBridge 30×50 mm 35-60% MeCN/H₂O (5 mMNH₄OH), 75 mL/min) to afford the title compound (60 mg, 0.145 mmol).

LCMS: RT: 2.53 min (LCMS Method 4) MS m/z 413.3 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.40 (d, J=9.3 Hz, 1H), 7.16 (t, J=7.5 Hz,2H), 6.95-6.83 (m, 3H), 4.10-3.91 (m, 4H), 3.81 (s, 3H), 3.19 (s, 2H),3.00 (s, 1H), 2.78 (s, 1H), 2.31 (dd, J=13.1, 7.2 Hz, 1H), 2.20 (s, 2H),2.12-1.91 (m, 3H), 1.83 (d, J=13.4 Hz, 5H), 1.64 (s, 1H).

Example 50:(R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(pyridazin-3-yl)-2-azaspiro[3.4]octane

(R)-2-(6-chloropyridazin-3-yl)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Example 5N, 60 mg, 0.145 mmol) was dissolved in MeOH (15 mL) andsubjected to the H-Cube™ with a 10% Pd/C catalyst cartridge for 25 minat 25° C. and 10 psi H₂. The resulting solution was concentrated andpurified via preparative HPLC (XBridge 30×50 mm 35-60% MeCN/H₂O (5 mMNH₄OH)) to afford the title compound (6.9 mg, 0.018 mmol).

LCMS: RT: 2.27 min (LCMS Method 4) MS m/z 379.5 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.45 (dd, J=4.4, 1.4 Hz, 1H), 7.38 (dd, J=9.0,4.5 Hz, 1H), 7.16 (t, J=7.5 Hz, 2H), 6.97-6.86 (m, 2H), 6.83 (dd, J=9.1,1.6 Hz, 1H), 4.11-3.91 (m, 4H), 3.81 (s, 3H), 3.21 (s, 2H), 3.01 (m,1H), 2.83 (s, 1H), 2.38-2.14 (m, 3H), 2.13-1.92 (m, 3H), 1.83 (m, 5H),1.71-1.57 (m, 1H).

Example 5P:(R)-6-(4-(5-chloro-2-methoxyphenyl)piperidin-1-yl)-2-(pyridazin-4-yl)-2-azaspiro[3.4]octane

Step 1: (R)-tert-butyl6-(4-(5-chloro-2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate

To a solution of (R)-tert-butyl6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate(Intermediate 80, 0.17 g, 0.43 mmol) in DMF (4.3 mL) under nitrogen at0° C. was added CBMG (0.11 g, 0.51 mmol) and then HCl (4.0M in dioxane,0.13 mL, 0.51 mmol) dropwise. After 20 minutes additional HCl (4.0 M indioxane, 0.13 mL, 0.51 mmol) was added and the reaction was allowed towarm to room temperature over 2.5 hours. The reaction was diluted withwater and EtOAc and basified with 0.1 N NaOH (pH ˜13). The water layerwas extracted with EtOAc (2×). All organic layers were combined, dilutedwith heptanes, washed with water (3×), and then with 0.1 N NaOH (3×),dried with MgSO₄, filtered and concentrated. The crude material waspurified by FCC (0-10% MeOH (10% NH₄OH): DCM) to afford the titlecompound (70 mg, 0.16 mmol) as a white solid.

LCMS: Rt: 0.83 min (LCMS Method 1) MS m/z 435.6 [M+H]⁺.

Step 2:(R)-6-(4-(5-chloro-2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octane

In a round bottom flask, to a solution of (R)-tert-butyl6-(4-(5-chloro-2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate(0.040 g, 0.092 mmol) in DCM (0.7 mL) under nitrogen was added TFA (0.21mL, 2.8 mmol). After 25 minutes the reaction was concentrated, taken upin MeOH (2.5 mL), and Isoelute Si-Propylsulfonic acid (SCX-2) resin(0.64 mmol/g, 0.43 g, 0.28 mmol) was added and this was stirred for 1hour. The resin was filtered and rinsed twice with MeOH to remove TFA.The resin was then washed with 7N Ammonia in Methanol (3×) to elute theproduct and these washes were concentrated to afford the title compound(32 mg, 0.096 mmol) as a colorless oil.

LCMS: Rt: 0.52 min (LCMS Method 1) MS m/z 335.5 [M+H]⁺.

Step 3:(R)-6-(4-(5-chloro-2-methoxyphenyl)piperidin-1-yl)-2-(3,6-dichloropyridazin-4-yl)-2-azaspiro[3.4]octane

In a round bottom flask, to a solution of(R)-6-(4-(5-chloro-2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(0.032 g, 0.096 mmol) in DMF (1.0 mL) was added K₂CO₃ (0.040 g, 0.29mmol) and 4-bromo-3,6-dichloropyridazine (0.024 g, 0.10 mmol). After 1hour the reaction was diluted with water, brine and EtOAc, and extractedwith EtOAc (3×). The combined organic layers were diluted with heptanes,washed with brine (2×), dried with MgSO₄, filtered and concentrated. Theresidue was purified by FCC (0-15% MeOH (10% NH₄OH): DCM) to afford thetitle compound (32 mg, 0.066 mmol) as an off-white solid.

LCMS: Rt: 0.78 min (LCMS Method 1) MS m/z 483.1 [M+H]⁺.

Step 4:(R)-6-(4-(5-chloro-2-methoxyphenyl)piperidin-1-yl)-2-(pyridazin-4-yl)-2-azaspiro[3.4]octane

In a 40 mL vial, SiliaCat Pd(0) (SiliCycle, 0.24 mmol/g, 0.028 g, 6.6μmol) was placed under nitrogen atmosphere. To this was added a solutionof(R)-6-(4-(5-chloro-2-methoxyphenyl)piperidin-1-yl)-2-(3,6-dichloropyridazin-4-yl)-2-azaspiro[3.4]octane(0.032 g, 0.066 mmol) in MeOH (0.66 mL). This was placed under ahydrogen balloon and the reaction was stirred at room temperature for 3days. The reaction was filtered through celite, rinsing with 1:1DCM:MeOH, and the filtrate was concentrated. This was purified bypreparative HPLC (XBridge C₁₈ OBD 30×50 mm 5 μm column MeCN/H₂Ow/5 mMNH₄OH 75 mL/min) to afford the title compound (6 mg, 0.014 mmol) as awhite solid.

LCMS: Rt: 0.78 min (LCMS Method 3) MS m/z 413.4 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.51 (d, J=6.2 Hz, 1H), 8.37 (d, J=3.0 Hz,1H), 7.19-7.09 (m, 2H), 6.96-6.86 (m, 1H), 6.53 (dd, J=6.3, 3.0 Hz, 1H),4.08-3.88 (m, 4H), 3.81 (s, 3H), 3.23-3.09 (m, 2H), 3.02-2.90 (m, 1H),2.82-2.68 (m, 1H), 2.30 (dd, J=12.9, 7.3 Hz, 1H), 2.23-2.10 (m, 2H),2.10-1.91 (m, 3H), 1.90-1.55 (m, 6H).

Example 5Q:(R)-6-(4-(2-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,5-triazin-2-yl)-2-azaspiro[3.4]octane

Step 1:(R)-2-(4-chloro-1,3,5-triazin-2-yl)-6-(4-(2-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane

In a round bottom flask, to a solution of(R)-6-(4-(2-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 41, 0.10 g, 0.26 mmol) in THE (2.6 mL) under nitrogen at−78° C. was added triethylamine (0.079 mL, 0.57 mmol) followed by asolution of 2,4-dichloro-1,3,5-triazine (0.042 g, 0.28 mmol) in THE (1.2mL) dropwise. After 10 minutes the reaction was warmed to roomtemperature, diluted with saturated aqueous sodium bicarbonate,extracted with DCM (3×), washed with brine, dried with MgSO₄, filteredand concentrated to afford the title compound (101 mg, 0.203 mmol) as alight yellow solid which was taken forward without further purification.

LCMS: Rt: 0.77 min (LCMS Method 1) MS m/z 498.4 [M+H]⁺.

Step 2:(R)-6-(4-(2-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,5-triazin-2-yl)-2-azaspiro[3.4]octane

In a round bottom flask, SiliaCat Pd(0) (SiliCycle, 0.20 mmol/g, 0.25 g,0.051 mmol) was placed under nitrogen atmosphere. To this was added asolution of(R)-2-(4-chloro-1,3,5-triazin-2-yl)-6-(4-(2-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(0.10 g, 0.20 mmol) in MeOH (6.8 mL). This was placed under a hydrogenballoon and the reaction was stirred at room temperature overnight. Thereaction was filtered through celite, rinsing with 1:1 DCM:MeOH, and thefiltrate was concentrated. The crude material was purified by reversephase C₁₈ FCC (20-70% MeCN:water, with 0.1% NH₄OH) to afford the titlecompound (46 mg, 0.095 mmol) as a white solid.

LCMS: Rt: 1.26 min (LCMS Method 3) MS m/z 464.5 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.47 (s, 2H), 7.24-7.09 (m, 2H), 6.99-6.86 (m,2H), 4.21-3.96 (m, 6H), 3.87 (d, J=6.0 Hz, 2H), 3.52 (m, 2H), 3.27-3.13(m, 2H), 3.11-2.96 (m, 1H), 2.82-2.65 (m, 1H), 2.37-2.24 (m, 1H),2.24-1.46 (m, 16H).

Example 5R:(R)-2-(3,6-dichloropyridazin-4-yl)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octane

To a solution of(R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 4Q, 140 mg, 0.466 mmol) and K₂CO₃ (193 mg, 1.398 mmol) inDMF (5 mL) was added 4-bromo-3,6-dichloropyridazine (117 mg, 0.513mmol). The reaction was stirred at room temperature for 18 hours. Thereaction mixture was then diluted with water and extracted EtOAc (3×25mL). The combined organic layers were washed with brine (3×10 mL), driedover magnesium sulfate, filtered, and concentrated. The resultingresidue was purified via FCC (0-10% MeOH (1% NH₄OH)/DCM to afford thetitle compound (100 mg, 0.212 mmol).

LCMS: RT: 2.90 min (LCMS Method 4) MS m/z: 447.3 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.15 (t, J=7.6 Hz, 2H), 6.94-6.85 (m, 2H),6.57 (s, 1H), 4.22 (m, 4H), 3.81 (s, 3H), 3.21-3.11 (m, 2H), 3.04-2.93(m, 1H), 2.78-2.68 (m, 1H), 2.28 (dd, J=12.9, 7.3 Hz, 1H), 2.15 (m, 2H),2.10-1.90 (m, 3H), 1.85-1.73 (m, 5H), 1.67-1.56 (m, 1H).

Example 5S:(R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(pyridazin-4-yl)-2-azaspiro[3.4]octane

(R)-2-(3,6-dichloropyridazin-4-yl)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Example 5R, 90 mg, 0.201 mmol) was dissolved in MeOH (15 mL) andsubjected to the H-Cube™ with a 10% Pd/C catalyst cartridge for 45 minat 25° C. and 10 psi H₂. The resulting solution was concentrated andpurified via FCC (0-10% MeOH (1% NH₄OH)/DCM) to afford the titlecompound (36.3 mg, 0.095 mmol).

LCMS: RT: 2.33 min (LCMS Method 4) MS m/z: 379.3 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.50 (d, J=5.9 Hz, 1H), 8.36 (d, J=3.0 Hz,1H), 7.16 (t, J=7.7 Hz, 2H), 6.95-6.83 (m, 2H), 6.53 (dd, J=6.3, 3.0 Hz,1H), 4.08-3.89 (m, 4H), 3.81 (s, 3H), 3.23-3.11 (m, 2H), 2.99 (m, 1H),2.75 (m, 1H), 2.30 (dd, J=12.9, 7.3 Hz, 1H), 2.16 (m, 2H), 2.10-1.91 (m,3H), 1.90-1.72 (m, 5H), 1.69-1.56 (m, 1H).

Example 5T:(R)-2-methyl-1-(2-(1-(2-(3-methylpyrazin-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)propan-2-ol

In a microwave vial, to a solution of(R)-1-(2-(1-(2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)-2-methylpropan-2-ol(Intermediate 4C, 110 mg, 0.307 mmol) in isopropanol (3 mL) at 0° C. wasadded triethylamine (0.094 mL, 0.675 mmol) followed by a solution of2-chloro-3-methylpyrazine (43.4 mg, 0.338 mmol) in isopropanol (0.5 mL).The reaction mixture was stirred at 0° C. for 10 min and then stirred at140° C. in the microwave for 2 hours. The reaction solvent wasevaporated and the residue purified via FCC (0-10% MeOH (1% NH₄OH)/DCM)to afford the title compound (21.3 mg, 0.046 mmol).

LCMS: RT: 2.37 min (LCMS Method 4) MS m/z: 451.5 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.90 (d, J=2.8 Hz, 1H), 7.70 (d, J=2.9 Hz,1H), 7.22-7.10 (m, 2H), 6.90 (t, J=7.5 Hz, 2H), 5.49 (s, 1H), 4.20-3.93(m, 4H), 3.77 (s, 2H), 3.21 (s, 4H), 3.15-3.01 (m, 1H), 2.77 (s, 1H),2.43 (s, 3H), 2.36-2.13 (m, 3H), 2.05 (m, 1H), 1.98-1.69 (m, 5H), 1.63(t, J=8.8 Hz, 1H), 1.35 (s, 6H).

Example 5U:(R)-1-(2-(1-(2-(1,3,5-triazin-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)-2-methylpropan-2-ol

Step 1:(R)-1-(2-(1-(2-(4-chloro-1,3,5-triazin-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)-2-methylpropan-2-ol

To a solution of(R)-1-(2-(1-(2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)-2-methylpropan-2-ol(Intermediate 4C, 75 mg, 0.209 mmol) in THE (2 mL) under nitrogen at−78° C. was added triethylamine (0.06 mL, 0.460 mmol) followed by asolution of 2,4-dichloro-1,3,5-triazine (34.5 mg, 0.230 mmol) in THE(0.5 mL). The reaction mixture was stirred at −78° C. for 15 min beforewarming to room temperature over 10 min. The reaction mixture wasdiluted with saturated aqueous sodium bicarbonate and extracted with DCM(3×25 mL). The combined organic extracts were washed with brine (1×25mL), dried over magnesium sulfate, filtered, and concentrated to affordthe title compound (99 mg, 0.209 mmol) that was used without furtherpurification.

LCMS: RT: 1.05 min (LCMS Method 2) MS m/z: 472.4 [M+H]⁺.

Step 2:(R)-1-(2-(1-(2-(1,3,5-triazin-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)-2-methylpropan-2-ol

(R)-1-(2-(1-(2-(4-chloro-1,3,5-triazin-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)-2-methylpropan-2-ol(100 mg, 0.212 mmol) was dissolved in MeOH (10 mL) and subjected to theH-Cube™ with a 10% Pd/C catalyst cartridge for 60 min at 35° C. and 13psi H₂. The resulting solution was concentrated and purified via FCC(0-10% MeOH (1% NH₄OH)/DCM) to afford the title compound (33.7 mg, 0.073mmol).

LCMS: RT: 2.05 min (LCMS Method 4) MS m/z: 438.4 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.45 (s, 2H), 7.25-7.09 (m, 2H), 6.90 (t,J=7.4 Hz, 2H), 4.20-3.97 (m, 4H), 3.77 (s, 2H), 3.26-3.07 (m, 3H), 2.75(d, J=9.0 Hz, 1H), 2.28 (dd, J=13.0, 7.3 Hz, 1H), 2.25-2.13 (m, 2H),2.09-1.93 (m, 3H), 1.93-1.82 (m, 3H), 1.75 (m, 2H), 1.68-1.57 (m, 1H),1.35 (s, 6H).

Example 5V:(R)-6-(4-(5-fluoro-2-methoxyphenyl)piperidin-1-yl)-2-(pyridazin-4-yl)-2-azaspiro[3.4]octane

Step 1:(R)-2-(3,6-dichloropyridazin-4-yl)-6-(4-(5-fluoro-2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octane

To a stirring solution of(R)-6-(4-(5-fluoro-2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 4U, 26 mg, 0.082 mmol) in DMF (3 mL),4-bromo-3,6-dichloropyridazine (20.5 mg, 0.090 mmol) was added, followedby potassium carbonate (33.9 mg, 0.245 mmol). The reaction mixture wasstirred at room temperature for 16 hr. The reaction was then dilutedwith water and extracted with EtOAc. The combined organic layers werewashed with brine, dried over magnesium sulfate, filtered, andconcentrated to afford the title compound that was used without furtherpurification (38 mg, 0.082 mmol).

LCMS: Rt: 1.23 min (LCMS Method 2) MS m/z 465.2 [M+H]⁺.

Step 2:(R)-6-(4-(5-fluoro-2-methoxyphenyl)piperidin-1-yl)-2-(pyridazin-4-yl)-2-azaspiro[3.4]octane

A solution of(R)-2-(3,6-dichloropyridazin-4-yl)-6-(4-(5-fluoro-2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(156 mg, 0.335 mmol) in MeOH (5 mL) was passed through the H-Cube™ at22° C. and 10 bar pressure of hydrogen using a 10% Pd/C cartridge for 2hrs. The solvent was removed under reduced pressure and the residue waspurified by FCC (0-10% MeOH (1% NH₄OH)/DCM) to afford the title compound(18 mg, 0.045 mmol).

LCMS: Rt: 0.52 min (LCMS Method 1) MS m/z 397.3 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.51 (d, J=6.1 Hz, 1H), 8.36 (d, J=2.9 Hz,1H), 6.97-6.82 (m, 3H), 6.53 (dd, J=6.2, 3.1 Hz, 1H), 4.12-3.87 (m, 4H),3.80 (s, 3H), 3.23-3.11 (m, 2H), 2.98 (m, 1H), 2.83-2.66 (m, 1H),2.36-2.23 (m, 1H), 2.22-1.42 (m, 11H).

Example 5W:(R)-6-(4-(3-fluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane

Into a vial was added(R)-6-(4-(3-fluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 4J, 100 mg, 0.277 mmol) followed by a solution of5-bromopyrimidine (48.5 mg, 0.305 mmol) in dioxane (3 mL) and this wasplaced under nitrogen. Pd(dba)₂ (15.95 mg, 0.028 mmol), xantphos (19.26mg, 0.033 mmol) and NaOtBu (53.3 mg, 0.555 mmol) were added and this wasstirred at 80° C. for 2 hr. The reaction was then cooled to roomtemperature, filtered, and rinsed through with MeCN and EtOAc. Thefiltrate was concentrated and the residue was purified by preparativeHPLC (XBridge 30×50 mm 35-60% MeCN/H₂O (5 mM NH₄OH), 75 mL/min) toafford the title compound (41 mg, 0.098 mmol).

LCMS: Rt: 2.19 min (LCMS Method 4) MS m/z 439.6 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.47 (s, 1H), 8.00 (s, 2H), 7.17-6.86 (m, 3H),5.12 (m, 1H), 4.92 (dd, J=7.5, 6.1 Hz, 2H), 4.84-4.78 (m, 2H), 4.01-3.75(m, 4H), 3.17 (m, 2H), 3.09-2.91 (m, 1H), 2.84-2.62 (m, 1H), 2.30 (dd,J=12.8, 7.2 Hz, 1H), 2.22-1.90 (m, 5H), 1.88-1.52 (m, 6H).

Example 5X:(R)-6-(4-(2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-2-(pyridazin-3-yl)-2-azaspiro[3.4]octane

Step 1:(R)-2-(6-chloropyridazin-3-yl)-6-(4-(2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane

To an IPA (2 mL) solution of(R)-6-(4-(2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 4E, 85 mg, 0.247 mmol) was added DIEA (0.215 mL, 1.234mmol) and 3,6-dichloropyridazine (76 mg, 0.493 mmol) and this wasstirred at 45° C. for 48 hours. The reaction was then concentrated underreduced pressure and was purified by FCC (0-5% MeOH/DCM) to afford thetitle compound. (65 mg, 0.141 mmol).

LCMS: Rt: 1.11 min (LCMS Method 2) MS m/z 457.4 [M+H]⁺.

Step 2:(R)-6-(4-(2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-2-(pyridazin-3-yl)-2-azaspiro[3.4]octane

To a MeOH (2 mL) solution of(R)-2-(6-chloropyridazin-3-yl)-6-(4-(2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(85 mg, 0.186 mmol) was added Pd—C (20 mg, 0.019 mmol). The resultingmixture was stirred under a hydrogen balloon for 4 hrs and the reactionwas then filtered through a celite plug, concentrated and purified bypreparative HPLC (XBridge C18 30×50 mm 35-60% MeCN/H₂O (5 mM NH₄OH), 75mL/min). It was further purified by FCC (0-5% MeOH (1% NH₄OH)/DCM) toafford the title compound (23.4 mg, 0.055 mmol) as a white solid.

LCMS: Rt: 0.72 min (LCMS Method 1) MS m/z 423.6 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.44 (dd, J=4.5, 1.2 Hz, 1H), 7.37 (dd, J=9.1,4.5 Hz, 1H), 7.23-7.10 (m, 2H), 6.95-6.88 (m, 2H), 6.81 (dd, J=9.0, 1.2Hz, 1H), 4.13-4.09 (m, 2H), 4.07-3.98 (m, 2H), 3.98-3.90 (m, 2H),3.78-3.73 (m, 2H), 3.43 (s, 3H), 3.20-3.11 (m, 2H), 3.04 (m, 1H),2.79-2.68 (m, 1H), 2.28 (dd, J=12.8, 7.2 Hz, 1H), 2.14 (m, 2H),2.10-1.91 (m, 3H), 1.88-1.56 (m, 6H).

Example 5Y:(R)-6-(4-(2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-2-(5-methylpyrazin-2-yl)-2-azaspiro[3.4]octane

To a toluene (1 mL) solution of(R)-6-(4-(2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 4E, 33 mg, 0.096 mmol) was added Pd₂(dba)₃ (17.54 mg,0.019 mmol), rac-BINAP (11.93 mg, 0.019 mmol), 2-bromo-5-methylpyrazine(24.86 mg, 0.144 mmol) and sodium tert-butoxide (13.81 mg, 0.144 mmol).The reaction mixture was stirred under N₂ at 110° C. for 2 hours and thereaction was then filtered through a celite plug, concentrated andpurified by preparative HPLC (XBridge C18 30×50 mm 45-70% MeCN/H₂O (5 mMNH₄OH), 75 mL/min) to afford the title compound (10.6 mg, 0.023 mmol) asa pale yellow oil.

LCMS: Rt: 2.51 min (LCMS Method 2) MS m/z 437.6 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.93 (s, 1H), 7.74 (d, J=1.4 Hz, 1H),7.24-7.11 (m, 2H), 6.99-6.89 (m, 2H), 4.20-4.10 (m, 2H), 4.05-3.96 (m,2H), 3.93 (q, J=7.8 Hz, 2H), 3.82-3.76 (m, 2H), 3.46 (s, 3H), 3.30-3.20(m, 2H), 3.18-3.05 (m, 1H), 2.89 (s, 1H), 2.50-2.21 (m, 6H), 2.08 (m,2H), 2.00 (m, 1H), 1.95-1.59 (m, 6H).

Example 5Z:(R)-6-(4-(2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-2-(pyridazin-4-yl)-2-azaspiro[3.4]octane

To an IPA (2 mL) solution of(R)-6-(4-(2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 4E, 78 mg, 0.226 mmol) was added DIEA (146 mg, 1.132 mmol)and 4-bromo-3,6-dichloropyridazine (56.8 mg, 0.249 mmol). The resultingmixture was stirred at 50° C. for 1.5 hours. The reaction was thenconcentrated under reduced pressure and purified by FCC (0-10% MeOH/DCM)to afford a white solid as(R)-2-(3,6-dichloropyridazin-4-yl)-6-(4-(2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane.This material was dissolved in MeOH (2 mL) and 10% Pd—C(24 mg, 0.023mmol) was added. The resulting mixture was stirred under a hydrogenballoon for 16 hours. The reaction was then filtered through a celiteplug concentrated, and purified by preparative HPLC (XBridge C18 30×50mm 35-60% MeCN/H₂O (5 mM NH₄OH), 75 mL/min) to afford the title compound(10.6 mg, 0.023 mmol) as a colorless oil.

LCMS: Rt: 2.21 min (LCMS Method 2) MS m/z 423.4 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.53 (d, J=6.3 Hz, 1H), 8.38 (d, J=2.8 Hz,1H), 7.24-7.11 (m, 2H), 6.93 (t, J=7.3 Hz, 2H), 6.55 (dd, J=6.2, 3.0 Hz,1H), 4.14 (dd, J=5.3, 3.9 Hz, 2H), 4.08-3.90 (m, 4H), 3.81-3.75 (m, 2H),3.45 (s, 3H), 3.18 (t, J=9.9 Hz, 2H), 3.07 (m, 1H), 2.76 (m, 1H), 2.31(dd, J=12.8, 7.3 Hz, 1H), 2.25-2.12 (m, 2H), 2.03 (m, 3H), 1.92-1.57 (m,6H).

Example 5AA:(R)-2-(5-fluoropyridin-3-yl)-6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane

A dioxane (3 mL) suspension of(R)-6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 4Y, 95 mg, 0.268 mmol), 3-bromo-5-fluoropyridine (66.0 mg,0.375 mmol), cesium carbonate (218 mg, 0.670 mmol) and BrettPhos Pd G3(24.29 mg, 0.027 mmol) was stirred at 90° C. under N₂ for 16 hours. Thereaction mixture was concentrated under reduced pressure, redissolved inMeOH, filtered through a celite plug and purified by preparative HPLC(XBridge C18 30×50 mm 45-70% MeCN/H₂O (5 mM NH₄OH), 75 mL/min) to affordthe title compound (53.8 mg, 0.118 mmol) as a cream colored solid.

LCMS: Rt: 2.75 min (LCMS Method 2) MS m/z 450.4 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.72 (d, J=2.4 Hz, 1H), 7.59 (t, J=2.0 Hz,1H), 7.29-7.22 (m, 2H), 7.19-7.13 (m, 2H), 6.67 (dt, J=11.0, 2.4 Hz,1H), 4.05 (dd, J=11.3, 4.2 Hz, 2H), 3.87 (q, J=7.3 Hz, 2H), 3.83-3.76(m, 2H), 3.60 (m, 2H), 3.24-3.07 (m, 3H), 2.92 (m, 1H), 2.75 (m, 1H),2.29 (dd, J=12.9, 7.2 Hz, 1H), 2.20 (m, 2H), 2.01 (m, 3H), 1.91-1.71 (m,7H), 1.63 (m, 3H).

Example 5BB:(R)-2-(pyrimidin-5-yl)-6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane

A dioxane (3 mL) suspension of(R)-6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 4Y, 97 mg, 0.274 mmol), 5-bromopyrimidine (60.9 mg, 0.383mmol), cesium carbonate (232 mg, 0.684 mmol) and BrettPhos Pd G3 (24.8mg, 0.027 mmol) was stirred at 90° C. under N₂ for 16 hours. Thereaction mixture was concentrated under reduced pressure, redissolved inMeOH, filtered through a celite plug and then purified by preparativeHPLC (XBridge C18 30×50 mm 35-60% MeCN/H₂O (5 mM NH₄OH), 75 mL/min) toafford the title compound (49 mg, 0.112 mmol) as a cream colored solid.

LCMS: Rt: 2.29 min (LCMS Method 2) MS m/z 433.9 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.47 (s, 1H), 8.01 (s, 2H), 7.26 (m, 2H),7.21-7.12 (m, 2H), 4.05 (dd, J=11.0, 4.3 Hz, 2H), 3.93 (q, J=7.3 Hz,2H), 3.89-3.83 (m, 2H), 3.60 (td, J=12.0, 1.9 Hz, 2H), 3.23-3.06 (m,3H), 2.92 (m, 1H), 2.82-2.70 (m, 1H), 2.31 (dd, J=12.8, 7.3 Hz, 1H),2.20 (m, 2H), 2.13-1.93 (m, 3H), 1.92-1.70 (m, 7H), 1.63 (m, 3H).

Example 5CC:(R)-2-(6-fluoropyridin-3-yl)-6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane

A dioxane (3 mL) suspension of(R)-6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 4Y, 99 mg, 0.279 mmol), 5-bromo-2-fluoropyridine (68.8 mg,0.391 mmol), cesium carbonate (227 mg, 0.698 mmol) and BrettPhos Pd G3(25.3 mg, 0.028 mmol) was stirred at 90° C. under N₂ for 16 hours. Thereaction mixture was concentrated under reduced pressure, redissolved inMeOH, filtered through a celite plug and purified by preparative HPLC(XBridge C18 30×50 mm 45-70% MeCN/H₂O (5 mM NH₄OH), 75 mL/min) to affordthe title compound (18.7 mg, 0.041 mmol) as a white solid.

LCMS: Rt: 2.77 min (LCMS Method 2) MS m/z 450.8 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.32 (dd, J=2.9, 1.8 Hz, 1H), 7.25 (m, 2H),7.19-7.13 (m, 2H), 7.06 (m, 1H), 6.88 (dd, J=8.8, 2.6 Hz, 1H), 4.11-3.99(m, 2H), 3.84-3.77 (m, 2H), 3.77-3.71 (m, 2H), 3.60 (m, 2H), 3.15 (m,3H), 2.91 (m, 1H), 2.74 (m, 1H), 2.28 (dd, J=12.8, 7.3 H/z, 1H), 2.19(m, 2H), 2.09-1.91 (m, 3H), 1.90-1.70 (m, 7H), 1.67-1.55 (m, 3H).

Example 5DD:(R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(5-methylpyrazin-2-yl)-2-azaspiro[3.4]octane

(R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 4Q, 75 mg, 0.250 mmol) was dissolved in IPA (2 mL) andcooled to 0° C. TEA (0.08 mL, 0.549 mmol) was added followed by2-chloro-5-methylpyrazine (35 mg, 0.275 mmol) dissolved in IPA (0.5 mL).The reaction was stirred for 10 min at 0° C. and then warmed to 50° C.and stirred for 16 hr. The reaction was then stirred at 150° C. for 2 hrand the solvent was concentrated. The residue was purified by FCC (0-10%MeOH (1% NH₄OH)/DCM) to yield the title compound (18 mg, 0.045 mmol).

LCMS: Rt: 2.55 min (LCMS Method 4) MS m/z 393.0 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.91 (d, J=1.4 Hz, 1H), 7.71 (d, J=1.8 Hz,1H), 7.19-7.11 (m, 2H), 6.95-6.84 (m, 2H), 4.04-3.85 (m, 4H), 3.81 (s,3H), 3.18 (s, 2H), 2.98 (m, 1H), 2.75 (s, 1H), 2.36 (s, 3H), 2.28 (dd,J=12.9, 7.4 Hz, 1H), 2.16 (d, J=12.8 Hz, 2H), 2.11-1.90 (m, 3H),1.87-1.70 (m, 5H), 1.70-1.56 (m, 1H).

Example 6A:(R)-(6-(4-(5-fluoro-2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone

To a stirring solution of oxetane-3-carboxylic acid (105 mg, 0.871 mmol)in DMF (5.0 mL), TBTU (280 mg, 0.871 mmol) was added. This was stirredfor 15 min at room temperature. The mixture was then added to a stirringsolution of(R)-6-(4-(5-fluoro-2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Example 4U, 185 mg, 0.581 mmol) and DIPEA (0.51 mL, 2.90 mmol) in DCM(10 mL). The reaction mixture was stirred at room temperature for 16 hr.The DCM was removed under reduced pressure and the remaining reactionmixture poured into EtOAc. This was washed with sat NaHCO₃, water andbrine then dried over Na₂SO₄. The solvent was removed under reducedpressure. The crude product was purified by preparative HPLC (XBridge30×50 mm 25-50% MeCN/H₂O (5 mM NH₄OH), 75 mL/min) to afford the titlecompound (18 mg, 0.042 mmol).

LCMS: Rt: 2.10 (LCMS Method 4) MS m/z 403.3 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.00-6.72 (m, 3H), 4.77 (dd, J=8.2, 2.0 Hz,4H), 4.09-3.73 (m, 8H), 3.21-3.04 (m, 2H), 2.96 (m, 1H), 2.68 (m, 1H),2.30-1.47 (m, 12H).

Example 6B:(R)-(6-(4-(2-(difluoromethoxy)-4-fluorophenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone

To a stirring solution of oxetane-3-carboxylic acid (42 mg, 0.346 mmol)in DMF (2 mL) and DCM (2.5 mL), TBTU (111 mg, 0.346 mmol) was added.This was stirred for 15 min at RT. The mixture was then added to astirring solution of(R)-6-(4-(2-(difluoromethoxy)-4-fluorophenyl)piperidin-1-yl)-2-azaspiro[3.4]octaneTFA salt (Intermediate 4V, 108 mg, 0.231 mmol) and DIPEA (0.201 mL,1.153 mmol) in DCM (10 mL). The reaction mixture was stirred at roomtemperature for 16 hr. The DCM was removed and the remaining reactionmixture poured into EtOAc. This was washed with sat NaHCO₃, water andbrine then dried over Na₂SO₄. The solvent was removed under reducedpressure and the crude product was purified by preparative HPLC (XBridge30×50 mm 35-60% MeCN/H₂O (5 mM NH₄OH), 75 mL/min) to afford the titlecompound (15 mg, 0.031 mmol).

LCMS: Rt: 1.03 min (LCMS Method 3) MS m/z 439.3, [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.34 (dd, J=8.6, 6.4 Hz, 1H), 7.14-6.62 (m,3H), 4.77 (dd, J=8.0, 2.0 Hz, 4H), 4.09-3.71 (m, 5H), 3.14 (m, 2H), 2.94(m, 1H), 2.78-2.60 (m, 1H), 2.27-2.06 (m, 3H), 2.02-1.85 (m, 3H),1.82-1.67 (m, 5H), 1.64-1.46 (m, 1H).

Example 6C:(R)-(6-(4-(4-fluoro-2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone

To a stirring solution of oxetane-3-carboxylic acid (115 mg, 0.961 mmol)in DMF (2 mL) and DCM (2.5 mL), TBTU (308 mg, 0.961 mmol) was added.This was stirred for 15 mins at RT and it was then added to a stirringsolution of(R)-6-(4-(4-fluoro-2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octaneTFA salt (Intermediate 4W, 277 mg, 0.641 mmol) and DIPEA (0.559 mL, 3.20mmol) in DCM (10 mL). The reaction mixture was stirred at roomtemperature for 16 hr. The DCM was removed and the residue was pouredinto EtOAc. This was washed with sat. NaHCO₃, water and brine then driedover Na₂SO₄. The solvent was removed under reduced pressure and thecrude product was purified by preparative HPLC (XBridge 30×50 mm 35-60%MeCN/H₂O (5 mM NH₄OH), 75 mL/min) to afford the title compound (23 mg,0.054 mmol).

LCMS: Rt: 2.12 min (LCMS Method 4) MS m/z 403.6 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 7.03 (dd, J=8.5, 6.7 Hz, 1H), 6.60-6.43 (m,2H), 4.82 (ddd, J=6.8, 5.6, 3.0 Hz, 2H), 4.72-4.58 (m, 2H), 3.93-3.64(m, 8H), 3.00 (s, 2H), 2.80 (m, 1H), 2.52 (s, 1H), 2.15-1.47 (m, 12H).

Example 6D:(R)-(6-(4-(4-fluoro-2-isopropoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone

To a stirring solution of oxetane-3-carboxylic acid (122 mg, 1.013 mmol)in DMF (2.5 mL) and DCM (2.5 mL), TBTU (325 mg, 1.013 mmol) was added.This was stirred for 15 min at room temperature and then the mixture wasthen added to a stirring solution of(R)-6-(4-(4-fluoro-2-isopropoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octaneTFA salt (Intermediate 4X, 311 mg, 0.675 mmol) and DIPEA (0.590 mL, 3.38mmol) in DCM (10 mL). The reaction mixture was stirred at roomtemperature for 16 hr. The DCM was removed and the residue was pouredinto EtOAc. This was washed with sat NaHCO₃, water and brine then driedover Na₂SO₄. The solvent was removed under reduced pressure and thecrude product was purified by preparative HPLC (XBridge 30×50 mm 35-60%MeCN/H₂O (5 mM NH₄OH), 75 mL/min) to afford the title compound (10 mg,0.022 mmol).

LCMS: Rt: 2.46 min (LCMS Method 4) MS m/z 431.5 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.13 (dd, J=8.6, 6.8 Hz, 1H), 6.69 (dd,J=11.3, 2.5 Hz, 1H), 6.58 (td, J=8.4, 2.5 Hz, 1H), 4.77 (dd, J=8.2, 2.0Hz, 4H), 4.57 (m, 1H), 4.06-3.78 (m, 5H), 3.13 (m, 2H), 2.90 (m, 1H),2.68 (m, 1H), 2.25-2.05 (m, 3H), 2.02-1.84 (m, 3H), 1.84-1.62 (m, 5H),1.57 (m, 1H), 1.32 (d, J=5.9 Hz, 6H).

Example 6E:(R)-(1-fluorocyclopropyl)(6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone

To a DCM (21 mL) solution of 1-fluorocyclopropanecarboxylic acid (0.754g, 6.88 mmol) was added TBTU (3.01 g, 9.38 mmol) and this was stirred atRT for 10 min. Next,(R)-6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 4Y, 2.41 g, 6.25 mmol) and DIEA (4.37 ml, 25.02 mmol) inDCM (21 mL) was added to the reaction. The resulting mixture was stirredat RT for 16 h. Separately, a second reaction using the same conditionswas also conducted with 1-fluorocyclopropanecarboxylic acid (161 mg,1.474 mmol), TBTU (645 mg, 2.010 mmol), DIEA (0.933 mL, 5.36 mmol) and(R)-6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(500 mg, 1.34 mmol). The two reactions were then combined andconcentrated and purified by successive FCC runs (04% 7N NH₃/MeOH/DCM);(7% MeOH/DCM); (6% 7N NH₃ in MeOH/40% EtOAc/heptanes); (3% 7N NH₃ inMeOH/EtOAc) to yield the title compound as a cream colored solid (2.04g, 4.58 mmol).

LCMS: Rt: 2.46 min (LCMS Method 4) MS m/z 441.8 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.27-7.24 (m, 2H), 7.17-7.13 (m, 2H),4.48-4.24 (m, 2H), 4.12-3.82 (m, 4H), 3.60 (td, J=11.9, 2.0 Hz, 2H),3.27-3.03 (m, 3H), 2.92 (tt, J=11.9, 3.9 Hz, 1H), 2.75 (s, 1H),2.37-2.12 (m, 3H), 2.10-1.68 (m, 10H), 1.68-1.55 (m, 3H), 1.35-1.18 (m,4H).

Example 7A:(R)-(6-(4-(2-cyclopropoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone

(R)-(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone(Intermediate 19A, 22 mg, 0.059 mmol) was dissolved in DMF (0.7 mL) andbromocyclopropane (20 μL, 0.25 mmol) was added, followed by Cs₂CO₃ (29.0mg, 0.089 mmol). The reaction mixture was heated at 175° C. in themicrowave for 2 hours. The reaction mixture was concentrated andpurified via preparative HPLC (XBridge 30×50 mm 35-60% MeCN/H₂O (5 mMNH₄OH) 75 mL/min) to afford the title compound (4.2 mg, 0.010 mmol) asan off-white solid.

LCMS: Rt: 2.33 min (LCMS Method 4) MS m/z 411.4 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 7.20 (d, J=7.34 Hz, 3H), 6.98-6.91 (m, 1H),5.00-4.85 (m, 2H), 4.80-4.65 (m, 2H), 4.04-3.64 (m, 6H), 3.16-2.99 (m,2H), 2.95-2.81 (m, 1H), 2.68-2.50 (m, 1H), 2.24-1.60 (m, 12H), 0.89-0.62(m, 4H).

Example 7B:(R)-(6-(4-(2-(2-fluoro-2-methylpropoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone

(R)-(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone(Intermediate 19A, 20 mg, 0.054 mmol), 1-bromo-2-fluoro-2-methylpropane(19 mg, 0.123 mmol) and Cs₂CO₃ (45 mg, 0.138 mmol) were dissolved in DMF(0.5 mL). The reaction mixture was stirred at 70° C. for 18 hours. Thecrude reaction mixture was purified via preparative HPLC (XBridge 30×50mm 35-60% MeCN/H₂O (5 mM NH₄OH) 75 mL/min) to afford the title compound(1.2 mg, 0.0026 mmol) as a white solid.

LCMS: RT: 2.32 min (LCMS Method 3) MS m/z 445.5 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 7.19 (d, J=14.18 Hz, 2H), 6.96 (s, 1H), 6.82(d, J=8.31 Hz, 1H), 4.97-4.88 (m, 2H), 4.78-4.69 (m, 2H), 3.94 (d,J=17.12 Hz, 7H), 3.20-2.93 (m, 3H), 2.68-2.54 (m, 1H), 2.26-1.64 (m,12H), 1.55 (s, 3H), 1.50 (s, 3H).

Example 7C:(R)-oxetan-3-yl(6-(4-(2-(thiazol-2-yloxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone

(R)-(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone(Intermediate 19A, 31 mg, 0.084 mmol), 2-bromothiazole (44 mg, 0.268mmol) and Cs₂CO₃ (32 mg, 0.098 mmol) were dissolved in DMF (0.75 mL).The reaction mixture was stirred at 100° C. for 18 hours at which timeadditional 2-bromothiazole (44 mg, 0.268 mmol) was added. The reactionmixture was heated at 110° C. for an additional 2 hours, thenconcentrated and purified via preparative HPLC (XBridge 30×50 mm 35-60%MeCN/H₂O (5 mM NH₄OH) 75 mL/min) to afford the title compound (7.5 mg,0.016 mmol) as an off-white solid.

LCMS: RT: 1.99 min (LCMS Method 3) MS m/z 454.5 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 7.43-7.35 (m, 1H), 7.27-7.19 (m, 4H),6.83-6.76 (m, 1H), 4.99-4.85-(m, 2H), 4.78-4.68 (m, 2H), 4.01-3.72 (m,5H), 3.15-2.98 (m, 2H), 2.95-2.81 (m, 1H), 2.65-2.49 (m, 1H), 2.22-2.06(m, 1H), 1.80 (d, J=6.85 Hz, 9H), 2.06-1.64 (m, 2H).

Example 7D:(R)-3-(2-(1-(2-(oxetane-3-carbonyl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)propanenitrile

(R)-(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone(Intermediate 19A, 18 mg, 0.049 mmol), triethylamine (6.77 μL, 0.049mmol), and acrylonitrile (1 mL, 0.049 mmol) were added to a vial and thereaction was stirred at 80° C. for 18 hours. Cs₂CO₃ (3 mg, 9.21 μmol),THE (0.5 mL) and additional acrylonitrile (1 mL, 0.049 mmol) were thenadded, and the reaction was heated at 80° C. for an additional 24 hours.The reaction mixture was concentrated, diluted with MeOH and purifiedvia preparative HPLC (XBridge 30×50 mm 25-50% MeCN/H₂O (5 mM NH₄OH)) toafford the title compound (13.2 mg, 0.030 mmol) as a cream coloredsolid.

LCMS: RT: 1.80 min (LCMS Method 3) MS m/z 424.3 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 7.38-7.31 (m, 1H), 7.27-7.16 (m, 1H),7.10-6.98 (m, 1H), 6.90-6.79 (m, 1H), 4.93 (d, J=5.87 Hz, 2H), 4.76 (s,2H), 4.24 (t, J=5.87 Hz, 2H), 4.04-3.64 (m, 6H), 3.38-2.52 (m, 8H), 1.88(m, 9H).

Example 7E:oxetan-3-yl((R)-6-(4-(2-(((R)-tetrahydrofuran-3-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone

(R)-(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone(Intermediate 19A, 16 mg, 0.043 mmol), (R)-(tetrahydrofuran-3-yl)methyl4-methylbenzenesulfonate (Intermediate 71, 20 mg, 0.078 mmol) and Cs₂CO₃(35.2 mg, 0.108 mmol) were dissolved in DMF (0.8 mL). The reaction wasstirred at 80° C. for 18 hours, then diluted with methanol and purifiedvia preparative HPLC (XBridge 30×50 mm 25-50% MeCN/H₂O (5 mM NH₄OH) 75mL/min) to afford the title compound (11.1 mg, 0.023 mmol).

LCMS: RT: 2.06 min (LCMS Method 3) MS m/z 455.5 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 7.19 (d, J=12.23 Hz, 2H), 6.94 (s, 1H), 6.84(d, J=8.31 Hz, 1H), 5.01-4.86 (m, 2H), 4.81-4.64 (m, 2H), 4.06-3.76 (m,11H), 3.75-3.66 (m, 1H), 3.19-3.05 (m, 2H), 3.02-2.87 (m, 1H), 2.85-2.71(m, 1H), 2.67-2.52 (m, 1H), 2.26-1.68 (m, 13H).

Example 7F:(R)-(6-(4-(2-isobutoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone

(R)-(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone(Intermediate 19A, 15 mg, 0.040 mmol) was dissolved in DMF (0.7 mL).Cs₂CO₃ (30 mg, 0.092 mmol) and 1-iodo-2-methylpropane (11 mg, 0.061mmol) were added and the reaction was stirred at room temperature. After3 days additional 1-iodo-2-methylpropane (11 mg, 0.061 mmol) was addedand the reaction was heated at 50° C. for 2 hours. The reaction was thencooled to room temperature, diluted with MeOH and purified directly bypreparative HPLC (XBridge 30×50 mm 45-70% MeCN/H₂O (5 mM NH₄OH) 75mL/min) to provide the title compound as a colorless oil (2.2 mg, 5.0μmol).

LCMS: Rt: 1.15 min (LCMS Method 2), MS m/z 427.4 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 7.27-7.24 (m, 1H), 7.24-7.16 (m, 1H),6.99-6.92 (m, 1H), 6.87-6.81 (m, 1H), 4.96-4.83 (m, 2H), 4.81-4.69 (m,2H), 4.27-4.23 (m, 1H), 3.98-3.68 (m, 7H), 3.33-3.15 (m, 2H), 2.85-2.69(m, 2H), 2.58-2.39 (m, 2H), 2.37-1.99 (m, 5H), 1.96-1.76 (m, 1H), 1.53(m, 4H), 1.04 (d, J=6.36 Hz, 6H).

Example 7G:(R)-(6-(4-(2-(cyclopentyloxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone

(R)-(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone(Intermediate 19A, 21 mg, 0.057 mmol) was dissolved in MeCN (0.8 mL).Cs₂CO₃ (50 mg, 0.15 mmol) and bromocyclopentane (0.020 mL, 0.19 mmol)were added and the reaction was heated at 60° C. for 5 hours thenstirred at room temperature for 16 hours. The reaction was purifieddirectly by preparative HPLC (XBridge 30×50 mm 35-60% MeCN/H₂O (5 mMNH₄OH) 75 mL/min) to provide the title compound as a white foam (11.8mg, 0.026 mmol).

LCMS: Rt: 0.82 min (LCMS Method 1), MS m/z 439.4 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 7.22 (m, 2H), 6.98-6.84 (m, 2H), 4.92 (dd,J=14.0, 7.6 Hz, 2H), 4.77 (td, J=14.6, 14.0, 8.3 Hz, 3H), 4.01-3.68 (m,5H), 3.19 (d, J=50.2 Hz, 2H), 2.76 (s, 2H), 2.50 (s, 2H), 2.22 (d,J=57.4 Hz, 2H), 2.08-1.61 (m, 13H). 3 peaks are obscured by the watersignal.

Example 7H:(R)-(6-(4-(2-cyclobutoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone

(R)-(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone(Intermediate 19A, 18 mg, 0.049 mmol) was dissolved in DMF (0.7 mL).Cs₂CO₃ (55 mg, 0.17 mmol) and bromocyclobutane (9.8 mg, 0.073 mmol) wereadded and the reaction was stirred at 65° C. for 16 hr. The reaction wasthen cooled to room temperature, diluted with MeOH and purified directlyby preparative HPLC (XBridge 30×50 mm 45-70% MeCN/H₂O (5 mM NH₄OH) 75mL/min) to provide the title compound as a white solid (9.9 mg, 0.023mmol).

LCMS: Rt: 1.12 min (LCMS Method 2), MS m/z 425.3 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 7.22 (d, J=7.5 Hz, 1H), 7.15 (s, 1H), 6.93 (t,J=7.4 Hz, 1H), 6.71 (d, J=8.2 Hz, 1H), 4.97-4.88 (m, 2H), 4.76 (ddd,J=9.0, 5.9, 4.1 Hz, 2H), 4.66 (p, J=7.2 Hz, 1H), 3.98-3.81 (m, 5H),3.18-2.95 (m, 3H), 2.63 (s, 1H), 2.54-2.39 (m, 3H), 2.23-1.65 (m, 15H).

Example 71:(R)-(6-(4-(2-(cyclopropylmethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone

(R)-(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone(Intermediate 19A, 7 mg, 0.046 mmol) was dissolved in DMF (0.75 mL).Cs₂CO₃ (45 mg, 0.14 mmol) and (iodomethyl)cyclopropane (12.5 mg, 0.069mmol) were added and the reaction was stirred at 60° C. for 16 hr. Thereaction was then cooled to room temperature, diluted with MeOH andpurified directly by preparative HPLC (XBridge 30×50 mm 35-60% MeCN/H₂O(5 mM NH₄OH) 75 mL/min) to provide the title compound as a sticky solid(8.6 mg, 0.020 mmol).

LCMS: Rt: 1.09 min (LCMS Method 2), MS m/z 425.4 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 7.25-7.09 (m, 2H), 6.96-6.89 (m, 1H), 6.83 (d,J=7.34 Hz, 1H), 4.97-4.85 (m, 2H), 4.80-4.67 (m, 2H), 3.85 (d, J=6.36Hz, 7H), 3.19-2.93 (m, 3H), 2.70-2.53 (m, 1H), 2.29-1.56 (m, 12H),1.34-1.15 (m, 1H), 0.67-0.52 (m, 2H), 0.42-0.28 (m, 2H).

Example 7J:(R)-(6-(4-(2-ethoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone

(R)-(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone(Intermediate 19A, 17 mg, 0.045 mmol) was dissolved in DMF (0.75 mL).Cs₂CO₃ (44 mg, 0.13 mmol) and ethyl iodide (5.5 μl, 0.068 mmol) wereadded and the reaction was stirred at room temperature for 16 hr. Thereaction was diluted with MeOH and purified directly by preparative HPLC(XBridge 30×50 mm 35-60% MeCN/H₂O (5 mM NH₄OH) 75 mL/min) to provide thetitle compound as a white solid (11.6 mg, 0.029 mmol).

LCMS: Rt: 0.66 min (LCMS Method 1), MS m/z 399.5 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 7.25-7.10 (m, 2H), 6.92 (t, J=7.58 Hz, 1H),6.85 (d, J=8.31 Hz, 1H), 4.97-4.86 (m, 2H), 4.74 (d, J=1.47 Hz, 2H),4.05 (q, J=6.85 Hz, 2H), 3.99-3.74 (m, 5H), 3.19-2.92 (m, 3H), 2.70-2.52(m, 1H), 1.83 (d, J=4.89 Hz, 12H), 1.42 (t, J=6.85 Hz, 3H).

Example 7K:(R)-(6-(4-(2-isopropoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone

(R)-(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone(Intermediate 19A, 10 mg, 0.027 mmol) was dissolved in DMF (0.8 mL).Cs₂CO₃ (45 mg, 0.14 mmol) and 2-iodopropane (9.2 mg, 0.054 mmol) wereadded and the reaction was stirred at room temperature for 16 hr. Thereaction was diluted with MeOH and purified directly by preparative HPLC(XBridge 30×50 mm 35-60% MeCN/H₂O (5 mM NH₄OH) 75 mL/min) to provide thetitle compound as a white foam (5.7 mg, 0.013 mmol).

LCMS: Rt: 1.05 min (LCMS Method 2), MS m/z 413.4 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 7.23-7.18 (m, 1H), 7.18-7.10 (m, 1H),6.94-6.81 (m, 2H), 4.96-4.87 (m, 2H), 4.78-4.70 (m, 2H), 4.60-4.47 (m,1H), 4.02-3.74 (m, 5H), 3.17-2.90 (m, 3H), 2.71-2.52 (m, 1H), 2.26-1.60(m, 12H), 1.34 (d, J=5.87 Hz, 6H).

Example 7L:(R)-(6-(4-(2-(2-hydroxy-2-methylpropoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone

(R)-(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone(Intermediate 19A, 15 mg, 0.040 mmol) was dissolved in DMF (0.4 mL).Cs₂CO₃ (30 mg, 0.092 mmol) and 2,2-dimethyloxirane (300 μL, 3.33 mmol)were added and the reaction was heated at 100° C. for 16 hr. Thereaction was then cooled to room temperature, concentrated, diluted withMeOH and purified directly by preparative HPLC (XBridge 30×50 mm 25-50%MeCN/H₂O (5 mM NH₄OH) 75 mL/min) to provide the title compound as awhite solid (6.7 mg, 0.015 mmol).

LCMS: Rt: 0.93 min (LCMS Method 2), MS m/z 443.4 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 7.13-7.25 (m, 2H), 6.92-7.00 (m, 1H),6.80-6.88 (m, 1H), 4.88-4.96 (m, 2H), 4.67-4.79 (m, 2H), 3.97-3.88 (m,2H), 3.85-3.75 (m, 6H), 3.04-3.23 (m, 2H), 2.90-3.01 (m, 1H), 2.51-2.67(m, 1H), 1.68-2.21 (m, 11H), 1.38 (s, 6H).

Example 7M:(R)-(1-fluorocyclopropyl)(6-(4-(2-(pyrimidin-2-ylmethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanoneor(S)-(1-fluorocyclopropyl)(6-(4-(2-(pyrimidin-2-ylmethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone

(R)-(1-fluorocyclopropyl)(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanoneor(S)-(1-fluorocyclopropyl)(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone(Intermediate 17F, 15.8 mg, 0.042 mmol), 2-(chloromethyl)pyrimidine(10.91 mg, 0.085 mmol) and Cs₂CO₃ (41.5 mg, 0.127 mmol) were dissolvedin DMF (Volume: 0.75 mL) and the reaction was stirred at 60° C. for 16hours. The reaction was then diluted with MeOH and purified bypreparative HPLC (XBridge C18 OBD 30×50 mm 5 μm column MeCN/H₂O w/5 mMNH₄OH 75 mL/min) to yield the title compound (12 mg, 0.025 mmol) as awhite solid.

LCMS: Rt: 0.95 min (LCMS Method 2), MS m/z 465.4 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 8.78 (d, J=4.89 Hz, 2H), 7.27-7.22 (m, 2H),7.16-7.06 (m, 1H), 6.95 (s, 1H), 6.88 (d, J=7.83 Hz, 1H), 5.33 (s, 2H),4.42-4.19 (m, 2H), 4.06-3.84 (m, 2H), 3.25-3.02 (m, 3H), 2.69-2.52 (m,1H), 2.28-2.16 (m, 1H), 2.15-2.03 (m, 2H), 1.92 (m, 5H), 1.83-1.69 (m,3H), 1.68-1.56 (m, 1H), 1.41-1.32 (m, 2H), 1.25-1.14 (m, 2H).

Example 7N:(R)-(1-fluorocyclopropyl)(6-(4-(2-(2-hydroxyethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanoneor(S)-(1-fluorocyclopropyl)(6-(4-(2-(2-hydroxyethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone

(R)-(1-fluorocyclopropyl)(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanoneor(S)-(1-fluorocyclopropyl)(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone(Intermediate 17F, 30 mg, 0.081 mmol),2-((tert-butyldimethylsilyl)oxy)ethyl 4-methylbenzenesulfonate(Intermediate 7J, 31.9 mg, 0.097 mmol) and Cs₂CO₃ (65.6 mg, 0.201 mmol)were dissolved in DMF (1.0 mL). The reaction mixture was stirred at roomtemperature for 18 hours and then concentrated. The residue wasdissolved in THE (1.5 mL) and tetrabutylammonium fluoride (1M in THF,0.25 mL, 0.250 mmol) was added. The reaction mixture was stirred at roomtemperature for 90 minutes, then quenched with water and methanol, andconcentrated. The crude residue was purified via preparative HPLC(XBridge 30×50 mm 35-60% MeCN/H₂O (5 mM NH₄OH) 75 mL/min) to afford thetitle compound (8.5 mg, 0.019 mmol) as a white solid.

LCMS: Rt: 2.11 min (LCMS Method 3) MS m/z 417.3 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 7.20 (d, J=16.14 Hz, 2H), 6.96 (s, 1H), 6.88(d, J=8.31 Hz, 1H), 4.41-4.22 (m, 2H), 4.11 (d, J=4.89 Hz, 2H), 4.00 (m,4H), 3.19-3.04 (m, 2H), 3.04-2.90 (m, 1H), 2.73-2.53 (m, 1H), 2.28-2.14(m, 1H), 2.13-1.88 (m, 5H), 1.82 (m, 4H), 1.73-1.54 (m, 3H), 1.43-1.31(m, 2H), 1.27-1.14 (m, 2H).

Example 70:(R)-(6-(4-(2-(cyclopropylmethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanoneor(R)-(6-(4-(2-(cyclopropylmethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone

(R)-(1-fluorocyclopropyl)(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanoneor(S)-(1-fluorocyclopropyl)(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone(Intermediate 17F, 15 mg, 0.040 mmol), (iodomethyl)cyclopropane (11 mg,0.060 mmol), and Cs₂CO₃ (39.4 mg, 0.121 mmol) were dissolved in DMF(0.75 mL). The reaction was stirred at room temperature for 18 hours,then diluted with methanol and purified via preparative HPLC (XBridge30×50 mm 35-60% MeCN/H₂O (5 mM NH₄OH) 75 mL/min) to afford the titlecompound (12.4 mg, 0.029 mmol) as a colorless oil.

LCMS: Rt: 2.93 min (LCMS Method 4) MS m/z 427.4 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 7.26-7.10 (m, 2H), 6.93 (s, 1H), 6.86-6.80 (m,1H), 4.46-4.28 (m, 1H), 4.27-4.22 (m, 1H), 4.08-3.92 (m, 1H), 3.90 (s,1H), 3.85 (d, J=6.36 Hz, 2H), 3.23-2.93 (m, 3H), 2.75-2.54 (m, 1H),2.33-2.16 (m, 1H), 2.16-1.60 (m, 10H), 1.43-1.11 (m, 6H), 0.67-0.53 (m,2H), 0.42-0.26 (m, 2H).

Example 7P:(R)-1-(2-(2-(1-(2-(1-fluorocyclopropane-1-carbonyl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)ethyl)pyrrolidin-2-oneformate salt or(S)-1-(2-(2-(1-(2-(1-fluorocyclopropane-1-carbonyl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)ethyl)pyrrolidin-2-oneformate salt

(R)-(1-fluorocyclopropyl)(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanoneor(S)-(1-fluorocyclopropyl)(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone(Intermediate 17F, 15 mg, 0.040 mmol), 2-(2-oxopyrrolidin-1-yl)ethyl4-methylbenzenesulfonate (Intermediate 7K, 22.8 mg, 0.081 mmol) andCs₂CO₃ (39.4 mg, 0.121 mmol) were dissolved in DMF (1.0 mL), and thereaction mixture was stirred at room temperature for 18 hours.Additional 2-(2-oxopyrrolidin-1-yl)ethyl 4-methylbenzenesulfonate(Intermediate 7K, 22.8 mg, 0.081 mmol) was added, and the reactionmixture was heated to 75° C. for 5 hours. The reaction mixture wasdiluted with methanol and purified via preparative HPLC (XBridge 30×50mm 15-40% MeCN/H₂O (0.1% formic acid) 75 mL/min) to afford the titlecompound (3.6 mg, 0.0067 mmol) as a formate salt.

LCMS: RT: 2.13 min (LCMS Method 3) MS m/z 484.4 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 8.54 (s, 1H), 7.25-7.15 (m, 2H), 7.02-6.90 (m,1H), 6.81 (d, J=8.31 Hz, 1H), 4.47-4.21 (m, 2H), 4.10 (s, 2H), 4.07-3.85(m, 2H), 3.78-3.69 (m, 2H), 3.59-3.49 (m, 2H), 3.44-3.24 (m, 2H),3.13-2.78 (m, 3H), 2.40 (s, 5H), 2.15-1.80 (m, 11H), 1.43-1.31 (m, 2H),1.27-1.14 (m, 2H).

Example 7Q:(R)-(1-fluorocyclopropyl)(6-(4-(2-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanoneor(S)-(1-fluorocyclopropyl)(6-(4-(2-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone

(R)-(1-fluorocyclopropyl)(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanoneor(S)-(1-fluorocyclopropyl)(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone(Intermediate 17F, 15 mg, 0.040 mmol), 4-(iodomethyl)tetrahydro-2H-pyran(18.2 mg, 0.081 mmol) and Cs₂CO₃ (39.4 mg, 0.121 mmol) were dissolved inDMF (0.75 mL) and stirred at room temperature for 18 hours. The reactionmixture was then diluted with methanol and purified via preparative HPLC(XBridge 30×50 mm 45-70% MeCN/H₂O (5 mM NH₄OH) 75 mL/min) to afford thetitle compound (5.6 mg, 0.012 mmol) as a sticky solid.

LCMS: RT: 2.72 min (LCMS Method 3) MS m/z 471.5 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 7.25-7.13 (m, 2H), 6.97-6.90 (m, 1H), 6.84 (d,J=8.31 Hz, 1H), 4.42-4.21 (m, 2H), 4.11-3.87 (m, 4H), 3.83 (d, J=6.36Hz, 2H), 3.55-3.42 (m, 2H), 3.19-3.08 (m, 2H), 3.03-2.91 (m, 1H),2.73-2.55 (m, 1H), 2.28-2.17 (m, 1H), 1.74 (m, 13H), 1.53-1.46 (m, 2H),1.42-1.32 (m, 2H), 1.30-1.14 (m, 3H).

Example 7R:(R)-(1-fluorocyclopropyl)(6-(4-(2-((5-methyl-1,3,4-thiadiazol-2-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanoneor(S)-(1-fluorocyclopropyl)(6-(4-(2-((5-methyl-1,3,4-thiadiazol-2-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone

(R)-(1-fluorocyclopropyl)(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanoneor(S)-(1-fluorocyclopropyl)(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone(Intermediate 17G, 12 mg, 0.032 mmol) was dissolved in DMF (0.75 mL).Cs₂CO₃ (31.5 mg, 0.097 mmol) and2-(chloromethyl)-5-methyl-1,3,4-thiadiazole (7.2 mg, 0.048 mmol) wereadded and the reaction was stirred at room temperature for 16 hours. Thereaction was diluted with MeOH and purified directly by preparative HPLC(XBridge 30×50 mm 35-60% MeCN/H₂O (5 mM NH₄OH) 75 mL/min) to provide thetitle compound as a white solid (10.8 mg, 0.022 mmol).

LCMS: Rt: 0.99 min (LCMS Method 2), MS m/z 485.3 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 7.27-7.24 (m, 1H), 7.23-7.16 (m, 1H),7.06-6.98 (m, 1H), 6.97-6.90 (m, 1H), 5.47 (s, 2H), 4.45-4.21 (m, 2H),4.06-3.93 (m, 1H), 3.90 (s, 1H), 3.21-3.09 (m, 2H), 3.05-2.93 (m, 1H),2.82 (s, 3H), 2.70-2.57 (m, 1H), 2.29-2.17 (m, 1H), 2.14-1.71 (m, 8H),1.56 (s, 3H), 1.36 (m, 2H), 1.27-1.15 (m, 2H).

Example 7S:(R)-(6-(4-(2-ethoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanoneor(S)-(6-(4-(2-ethoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone

(R)-(1-fluorocyclopropyl)(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanoneor(S)-(1-fluorocyclopropyl)(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone(Intermediate 17G, 15 mg, 0.040 mmol) was dissolved in DMF (0.75 mL).Cs₂CO₃ (39 mg, 0.12 mmol) and iodoethane (9.4 mg, 0.060 mmol) were addedand the reaction was stirred at room temperature for 16 hr. The reactionwas diluted with MeOH and purified directly by preparative HPLC (XBridge30×50 mm 45-70% MeCN/H₂O (5 mM NH₄OH) 75 mL/min) to provide the titlecompound as a colorless oil (10.5 mg, 0.026 mmol).

LCMS: Rt: 0.78 min (LCMS Method 2), MS m/z 401.4 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 7.22 (d, J=7.82 Hz, 1H), 7.19-7.13 (m, 1H),6.92 (s, 1H), 6.85 (d, J=7.34 Hz, 1H), 4.42-4.28 (m, 1H), 4.27-4.22 (m,1H), 4.06-3.86 (m, 4H), 3.19-3.06 (m, 2H), 3.05-2.94 (m, 1H), 2.71-2.55(m, 1H), 2.28-2.16 (m, 1H), 2.14-1.61 (m, 11H), 1.43 (t, J=7.09 Hz, 3H),1.39-1.31 (m, 2H), 1.20 (m, 2H).

Example 7T:(R)-(6-(4-(2-(cyclopropylmethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanoneor(R)-(6-(4-(2-(cyclopropylmethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone

(R)-(1-fluorocyclopropyl)(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanoneor(S)-(1-fluorocyclopropyl)(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone(Intermediate 17G, 15 mg, 0.040 mmol) was dissolved in DMF (0.75 mL).Cs₂CO₃ (39 mg, 0.12 mmol) and (iodomethyl)cyclopropane (11 mg, 0.060mmol) were added and the reaction was stirred at room temperature for 16hr. The reaction was diluted with MeOH and purified directly bypreparative HPLC (XBridge 30×50 mm 55-80% MeCN/H₂O (5 mM NH₄OH) 75mL/min) to provide the title compound as a colorless oil (14.1 mg, 0.032mmol).

LCMS: Rt: 1.28 min (LCMS Method 2), MS m/z 427.4 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 7.26-7.10 (m, 2H), 6.93 (s, 1H), 6.86-6.80 (m,1H), 4.46-4.28 (m, 1H), 4.27-4.22 (m, 1H), 4.08-3.92 (m, 1H), 3.90 (s,1H), 3.85 (d, J=6.36 Hz, 2H), 3.23-2.93 (m, 3H), 2.75-2.54 (m, 1H),2.33-2.16 (m, 1H), 2.16-1.60 (m, 10H), 1.43-1.11 (m, 6H), 0.67-0.53 (m,2H), 0.42-0.26 (m, 2H).

Example 7U:(R)-(6-(4-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanoneor(S)-(6-(4-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone

(R)-(1-fluorocyclopropyl)(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanoneor(S)-(1-fluorocyclopropyl)(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone(Intermediate 17G, 18 mg, 0.048 mmol) was dissolved in DMF (0.7 mL).Cs₂CO₃ (31 mg, 0.097 mmol) and 4-(chloromethyl)-3,5-dimethylisoxazole(10.5 mg, 0.072 mmol) were added and the reaction was stirred at roomtemperature for 16 hr. The reaction was diluted with MeOH and purifieddirectly by preparative HPLC (XBridge 30×50 mm 35-60% MeCN/H₂O (5 mMNH₄OH) 75 mL/min) to provide the title compound as a white solid (16.9mg, 0.034 mmol).

LCMS: Rt: 1.09 min (LCMS Method 2), MS m/z 482.4 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 7.26-7.16 (m, 2H), 7.01-6.94 (m, 2H), 4.79 (s,2H), 4.38-4.27 (m, 1H), 4.24 (s, 1H), 3.96 (d, J=13.6 Hz, 1H), 3.88 (s,1H), 3.07 (s, 2H), 2.89 (s, 1H), 2.58 (s, 1H), 2.38 (s, 3H), 2.29 (s,3H), 2.18 (s, 1H), 1.93 (d, J=27.8 Hz, 4H), 1.73 (s, 4H), 1.35 (d, J=7.4Hz, 2H), 1.27-1.12 (m, 2H). 3 protons are obscured by the HDO peak.

Example 7V:(R)-(1-fluorocyclopropyl)(6-(4-(2-((2-methyloxazol-5-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanoneor(S)-(1-fluorocyclopropyl)(6-(4-(2-((2-methyloxazol-5-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone

(R)-(1-fluorocyclopropyl)(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanoneor(S)-(1-fluorocyclopropyl)(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone(Intermediate 17G, 15 mg, 0.040 mmol) was dissolved in DMF (0.75 mL).Cs₂CO₃ (39 mg, 0.12 mmol) and 5-(chloromethyl)-2-methyloxazole (7.9 mg,0.060 mmol) were added and the reaction was stirred at room temperaturefor 16 hours. The reaction was diluted with MeOH and purified directlyby preparative HPLC (XBridge 30×50 mm 35-60% MeCN/H₂O (5 mM NH₄OH) 75mL/min) to provide the title compound as a sticky solid (14.8 mg, 0.032mmol).

LCMS: Rt: 0.75 min (LCMS Method 1), MS m/z 468.4 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 7.28-7.15 (m, 2H), 7.06-6.92 (m, 3H), 5.04 (s,2H), 4.44-4.22 (m, 2H), 4.08-3.86 (m, 2H), 3.52 (d, J=4.8 Hz, 1H),3.19-2.88 (m, 3H), 2.73-2.54 (m, 1H), 2.50 (s, 3H), 2.31-2.15 (m, 1H),2.14-1.61 (m, 10H), 1.44-1.32 (m, 2H), 1.28-1.14 (m, 2H).

Example 7W:(R)-(1-fluorocyclopropyl)(6-(4-(2-((5-methyl-1,3,4-oxadiazol-2-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanoneor(S)-(1-fluorocyclopropyl)(6-(4-(2-((5-methyl-1,3,4-oxadiazol-2-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone

To a DMF (1 mL) solution of(R)-(1-fluorocyclopropyl)(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanoneor(S)-(1-fluorocyclopropyl)(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone(Intermediate 17F, 30 mg, 0.081 mmol) and cesium carbonate (79 mg, 0.242mmol), was added 2-(chloromethyl)-5-methyl-1,3,4-oxadiazole (12.81 mg,0.097 mmol). The resulting mixture was stirred at room temperature for16 hr. The crude mixture was diluted with DCM (20 mL) and washed withwater (2×20 mL). The organics were dried over MgSO₄ and concentrated.The residue was then purified by preparative HPLC (XBridge 30×50 mm25-50% MeCN/H₂O (5 mM NH₄OH)) to afford the title compound as a clearoil (27.5 mg, 0.058 mmol).

LCMS: Rt: 1.11 min (LCMS Method 3) MS m/z 469.5 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.23 (dd, J=7.7, 1.4 Hz, 1H), 7.18 (td, J=7.8,1.7 Hz, 1H), 7.07 (dd, J=8.2, 0.8 Hz, 1H), 6.99 (td, J=7.4, 0.8 Hz, 1H),5.31 (s, 2H), 4.45-4.23 (m, 2H), 4.03-3.83 (m, 2H), 3.19-3.09 (m, 2H),3.00 (m, 1H), 2.76-2.61 (m, 1H), 2.55 (s, 3H), 2.24 (m, 1H), 2.12 (m,2H), 2.05-1.86 (m, 3H), 1.86-1.67 (m, 5H), 1.58 (m, 1H), 1.30-1.17 (m,4H).

Example 7X:(R)-(1-fluorocyclopropyl)(6-(4-(2-((5-methyl-1,2,4-oxadiazol-3-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanoneor(S)-(1-fluorocyclopropyl)(6-(4-(2-((5-methyl-1,2,4-oxadiazol-3-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone

To a DMF (1 mL) solution of(R)-(1-fluorocyclopropyl)(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanoneor(S)-(1-fluorocyclopropyl)(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone(Intermediate 17F, 30 mg, 0.081 mmol) and cesium carbonate (79 mg, 0.242mmol), was added 3-(chloromethyl)-5-methyl-1,2,4-oxadiazole (12.81 mg,0.097 mmol). The resulting mixture was stirred at room temperature for16 hr. The crude mixture was diluted with DCM (20 mL) and washed withwater (2×20 mL). The organics were dried over MgSO₄ and concentrated.The residue was purified by preparative HPLC (XBridge 30×50 mm 25-50%MeCN/H₂O (5 mM NH₄OH)) to afford the title compound as a clear oil (28.2mg, 0.060 mmol).

LCMS: Rt: 0.71 min (LCMS Method 4) MS m/z 469.2 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.23 (dd, J=7.6, 1.4 Hz, 1H), 7.20-7.15 (m,1H), 7.11-7.05 (m, 1H), 6.99 (td, J=7.4, 0.8 Hz, 1H), 5.31 (s, 2H),4.48-4.23 (m, 2H), 4.04-3.82 (m, 2H), 3.19-3.09 (m, 2H), 3.00 (m, 1H),2.76-2.62 (m, 1H), 2.55 (s, 3H), 2.24 (m, 1H), 2.12 (m, 2H), 2.05-1.86(m, 3H), 1.78 (m, 5H), 1.58 (m, 1H), 1.32-1.19 (m, 4H).

Example 7Y:(R)-(1-fluorocyclopropyl)(6-(4-(2-((5-methyl-1,3,4-oxadiazol-2-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanoneor(S)-(1-fluorocyclopropyl)(6-(4-(2-((5-methyl-1,3,4-oxadiazol-2-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone

To a DMF (1 mL) solution of(R)-(1-fluorocyclopropyl)(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanoneor(S)-(1-fluorocyclopropyl)(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone(Intermediate 17G, 30 mg, 0.081 mmol) and cesium carbonate (79 mg, 0.242mmol), was added 2-(chloromethyl)-5-methyl-1,3,4-oxadiazole (12.81 mg,0.097 mmol). The resulting mixture was stirred at room temperature for16 hr. The crude mixture was diluted with DCM (20 mL) and washed withwater (2×20 mL). The organics were dried over MgSO₄ and concentrated.The residue was purified by preparative HPLC (XBridge 30×50 mm 25-50%MeCN/H₂O (5 mM NH₄OH)) to afford the title compound as a clear oil (29.4mg, 0.062 mmol).

LCMS: Rt: 2.40 min (LCMS Method 4) MS m/z 469.4 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.21 (dd, J=7.5, 1.4 Hz, 1H), 7.18-7.12 (m,1H), 7.05 (d, J=7.3 Hz, 1H), 6.96 (td, J=7.4, 0.8 Hz, 1H), 5.18 (s, 2H),4.45-4.24 (m, 2H), 4.03-3.83 (m, 2H), 3.18-3.10 (m, 2H), 3.04 (m, 1H),2.75-2.64 (m, 1H), 2.61 (s, 3H), 2.24 (m, 1H), 2.12 (m, 2H), 2.04-1.89(m, 3H), 1.87-1.66 (m, 5H), 1.58 (m, 1H), 1.31-1.20 (m, 4H).

Example 7Z:(R)-(1-fluorocyclopropyl)(6-(4-(2-((5-methyl-1,2,4-oxadiazol-3-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanoneor(S)-(1-fluorocyclopropyl)(6-(4-(2-((5-methyl-1,2,4-oxadiazol-3-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone

To a DMF (1 mL) solution of(R)-(1-fluorocyclopropyl)(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanoneor(S)-(1-fluorocyclopropyl)(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone(Intermediate 17G, 30 mg, 0.081 mmol) and cesium carbonate (79 mg, 0.242mmol), was added 3-(chloromethyl)-5-methyl-1,2,4-oxadiazole (12.81 mg,0.097 mmol). The resulting mixture was stirred at room temperature for16 hr. The crude mixture was diluted with DCM (20 mL) and washed withwater (2×20 mL). The organics were dried over MgSO₄ and concentrated.The residue was purified by preparative HPLC (XBridge 30×50 mm 25-50%MeCN/H₂O (5 mM NH₄OH)) to afford the title compound as a clear oil (27.5mg, 0.058 mmol).

LCMS: Rt: 2.39 min (LCMS Method 4) MS m/z 468.9 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.21 (dd, J=7.5, 1.4 Hz, 1H), 7.16 (td, J=7.7,1.7 Hz, 1H), 7.05 (dd, J=8.2, 0.7 Hz, 1H), 6.96 (td, J=7.4, 0.8 Hz, 1H),5.18 (s, 2H), 4.44-4.23 (m, 2H), 4.04-3.83 (m, 2H), 3.18-3.10 (m, 2H),3.04 (m, 1H), 2.68 (q, J=8.3 Hz, 1H), 2.61 (s, 3H), 2.24 (m, 1H), 2.12(m, 2H), 2.06-1.88 (m, 3H), 1.87-1.66 (m, 5H), 1.57 (m, 1H), 1.32-1.18(m, 4H).

Example 7AA:(R)-(1-fluorocyclopropyl)(6-(4-(2-(3,3,3-trifluoropropoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanoneor(S)-(1-fluorocyclopropyl)(6-(4-(2-(3,3,3-trifluoropropoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone

To a THF (1 mL) solution of(R)-(1-fluorocyclopropyl)(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanoneor(S)-(1-fluorocyclopropyl)(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone(Intermediate 17F, 20 mg, 0.054 mmol) was added3,3,3-trifluoropropan-1-ol (12.25 mg, 0.107 mmol), triphenylphosphine(28.2 mg, 0.107 mmol) and di-tert-butyl azodicarboxylate (24.73 mg,0.107 mmol). The resulting mixture was stirred at RT for 72 hr. Further3,3,3-trifluoropropan-1-ol (12.25 mg, 0.107 mmol) and di-tert-butylazodicarboxylate (24.73 mg, 0.107 mmol) were added at 24 and 48 hr afterinitializing the reaction. The reaction mixture was passed through a SCXresin cartridge, the cartridge was washed multiple times with DCM andMeOH before eluting with 7N NH₃ in MeOH. The MeOH solution wasconcentrated and the residue was purified by preparative HPLC (XBridge30×50 mm 45-70% MeCN/H₂O (5 mM NH₄OH)) to afford the title compound as aclear oil (3 mg, 0.006 mmol).

LCMS: Rt: 2.77 min (LCMS Method 4) MS m/z 469.3 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.27-7.12 (m, 2H), 6.95 (t, J=7.5 Hz, 2H),4.48-4.28 (m, 2H), 4.24 (t, J=5.9 Hz, 2H), 4.07-3.86 (m, 2H), 3.17 (dd,J=10.4, 4.9 Hz, 2H), 3.04 (m, 1H), 2.73 (m, 3H), 2.28 (m, 1H), 2.15 (q,J=9.6 Hz, 2H), 1.99 (m, 3H), 1.88-1.48 (m, 6H), 1.36-1.19 (m, 4H).

Example 7BB:(R)-(1-fluorocyclopropyl)(6-(4-(2-(3-hydroxy-3-methylbutoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanoneor(S)-(1-fluorocyclopropyl)(6-(4-(2-(3-hydroxy-3-methylbutoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone

To a DMF (0.5 mL) solution of(R)-(1-fluorocyclopropyl)(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanoneor(S)-(1-fluorocyclopropyl)(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone(Intermediate 17F, 20 mg, 0.054 mmol) and cesium carbonate (52.5 mg,0.161 mmol), was added 3-hydroxy-3-methylbutyl 4-methylbenzenesulfonate(16.65 mg, 0.064 mmol). The resulting mixture was stirred at roomtemperature for 16 hr. The crude mixture was diluted with DCM (20 mL)and washed with water (2×20 mL). The organics were dried over MgSO₄ andconcentrated. The residue was purified by preparative HPLC (XBridge30×50 mm 35-60% MeCN/H₂O (5 mM NH₄OH)) to afford the title compound as aclear oil (19.6 mg, 0.042 mmol).

LCMS: Rt: 2.39 min (LCMS Method 4) MS m/z 459.5 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.26-7.10 (m, 2H), 6.98-6.85 (m, 2H),4.50-4.23 (m, 2H), 4.14 (t, J=6.7 Hz, 2H), 4.07-3.84 (m, 2H), 3.17 (d,J=11.0 Hz, 2H), 3.03 (m, 1H), 2.78-2.64 (m, 1H), 2.32-2.22 (m, 1H), 2.13(q, J=10.2 Hz, 2H), 2.07-1.89 (m, 5H), 1.89-1.68 (m, 5H), 1.60 (m, 1H),1.35-1.22 (m, 10H).

Example 7CC:(R)-(6-(4-(2-(3-hydroxy-3-methylbutoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone

To a DMF (1 mL) solution of((R)-(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone)(Intermediate 19A, 20 mg, 0.054 mmol) and cesium carbonate (35.2 mg,0.108 mmol), was added 3-hydroxy-3-methylbutyl 4-methylbenzenesulfonate(18.13 mg, 0.070 mmol). The resulting mixture was stirred at roomtemperature for 16 hr. The crude mixture was diluted with DCM (20 mL)and washed with water (2×20 mL). The organics were dried over MgSO₄ andconcentrated. The residue was purified by preparative HPLC (XBridge30×50 mm 25-50% MeCN/H₂O (5 mM NH₄OH)) to afford the title compound as aclear oil (10.4 mg, 0.023 mmol).

LCMS: Rt: 1.92 min (LCMS Method 4) MS m/z 457.7 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.21-7.13 (m, 2H), 6.97-6.87 (m, 2H),4.84-4.76 (m, 4H), 4.14 (t, J=6.7 Hz, 2H), 4.08-3.80 (m, 5H), 3.16 (dt,J=9.5, 5.8 Hz, 2H), 3.09-2.96 (m, 1H), 2.70 (m, 1H), 2.22 (dd, J=12.8,7.3 Hz, 1H), 2.18-2.07 (m, 2H), 2.06-1.68 (m, 10H), 1.67-1.52 (m, 1H),1.32 (s, 6H).

Example 7DD:(R)-oxetan-3-yl(6-(4-(2-(2-(trifluoromethoxy)ethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone

To a DMF (1 mL) solution of((R)-(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone)(Intermediate 19A, 20 mg, 0.054 mmol) and cesium carbonate (35.2 mg,0.108 mmol), was added 1-bromo-2-(trifluoromethoxy)ethane (20.83 mg,0.108 mmol). The resulting mixture was stirred at room temperature for16 hr. The crude mixture was diluted with DCM (20 mL) and washed withwater (2×20 mL). The organics were dried over MgSO₄ and concentrated.The residue was purified by preparative HPLC (XBridge 30×50 mm 35-60%MeCN/H₂O (5 mM NH₄OH)) to afford the title compound as a clear oil (16.4mg, 0.033 mmol).

LCMS: Rt: 1.34 min (LCMS Method 3) MS m/z 483.3 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.26-7.13 (m, 2H), 6.96 (td, J=8.2, 1.9 Hz,2H), 4.84-4.75 (m, 4H), 4.42-4.36 (m, 2H), 4.27-4.22 (m, 2H), 4.08-3.80(m, 5H), 3.23-3.13 (m, 2H), 3.06 (m, 1H), 2.73 (m, 1H), 2.20 (m, 3H),2.07-1.84 (m, 5H), 1.83-1.69 (m, 3H), 1.67-1.53 (m, 1H).

Example 7EE:(R)-oxetan-3-yl(6-(4-(2-(2-(oxetan-3-yloxy)ethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone

To a DMF (1 mL) solution of((R)-(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone)(Intermediate 19A, 19 mg, 0.051 mmol) and cesium carbonate (33.4 mg,0.103 mmol), was added 2-(oxetan-3-yloxy)ethyl 4-methylbenzenesulfonate(Intermediate 7L, 15.36 mg, 0.056 mmol). The resulting mixture wasstirred at room temperature for 16 hr. The crude mixture was dilutedwith DCM (20 mL) and washed with water (2×20 mL). The organics weredried over MgSO₄ and concentrated. The residue was purified bypreparative HPLC (XBridge 30×50 mm 15-40% MeCN/H₂O (5 mM NH₄OH)) toafford the title compound as a clear oil (17.6 mg, 0.037 mmol).

LCMS: Rt: 0.97 min (LCMS Method 3) MS m/z 471.3 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.25-7.11 (m, 2H), 6.99-6.89 (m, 2H),4.86-4.76 (m, 6H), 4.71 (p, J=5.4 Hz, 1H), 4.61 (dd, J=6.7, 5.2 Hz, 2H),4.13 (dd, J=5.4, 3.6 Hz, 2H), 4.07-3.75 (m, 7H), 3.17 (t, J=9.0 Hz, 2H),3.07 (m, 1H), 2.71 (m, 1H), 2.29-2.12 (m, 3H), 2.08-1.85 (m, 5H),1.84-1.70 (m, 3H), 1.67-1.51 (m, 1H).

Example 7FF:(R)-(1-fluorocyclopropyl)(6-(4-(2-(3-methoxy-3-methylbutoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanoneor(S)-(1-fluorocyclopropyl)(6-(4-(2-(3-methoxy-3-methylbutoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone

To a DMF (0.5 mL) solution of(R)-(1-fluorocyclopropyl)(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanoneor(S)-(1-fluorocyclopropyl)(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone(Intermediate 17F, 8 mg, 0.021 mmol) and cesium carbonate (20.99 mg,0.064 mmol), was added 3-methoxy-3-methylbutyl 4-methylbenzenesulfonate(Intermediate 7M, 7.02 mg, 0.026 mmol). The resulting mixture wasstirred at room temperature for 16 hr. The crude mixture was dilutedwith DCM (20 mL) and washed with water (2×20 mL). The organics weredried over MgSO₄ and concentrated. The residue was purified bypreparative HPLC (XBridge 30×50 mm 45-70% MeCN/H₂O (5 mM NH₄OH)) toafford the title compound as a clear oil (6.8 mg, 0.014 mmol).

LCMS: Rt: 1.50 min (LCMS Method 3) MS m/z 473.4 [M+H]⁺.

1H NMR (400 MHz, CD₃OD) δ 7.26-7.11 (m, 2H), 6.99-6.83 (m, 2H),4.50-4.25 (m, 2H), 4.09 (t, J=6.8 Hz, 2H), 4.05-3.86 (m, 2H), 3.26 (s,3H), 3.22-3.13 (m, 2H), 3.04 (m, 1H), 2.78-2.65 (m, 1H), 2.27 (m, 1H),2.14 (q, J=9.4 Hz, 2H), 2.08-1.88 (m, 5H), 1.88-1.68 (m, 5H), 1.68-1.54(m, 1H), 1.33-1.22 (m, 10H).

Example 7GG:(R)-oxetan-3-yl(6-(4-(2-(3,3,3-trifluoropropoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone

To a EtOH (0.5 mL) solution of((R)-(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone)(Intermediate 19A, 24 mg, 0.065 mmol) and potassium carbonate (26.9 mg,0.194 mmol) was added 3,3,3-trifluoropropyl 4-methylbenzenesulfonate(16.66 mg, 0.062 mmol). The resulting mixture was stirred at 90° C. for72 hr. The crude mixture was diluted with DCM (20 mL) and washed withwater (2×20 mL). The organics were dried over MgSO₄ and concentrated.The residue was purified by preparative HPLC (XBridge 30×50 mm 35-60%MeCN/H₂O (5 mM NH₄OH)) to afford the title compound as a white solid(7.2 mg, 0.015 mmol).

LCMS: Rt: 2.30 min (LCMS Method 4) MS m/z 467.4 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.26-7.13 (m, 2H), 6.96 (t, J=7.3 Hz, 2H),4.83-4.76 (m, 4H), 4.24 (t, J=5.8 Hz, 2H), 4.08-3.81 (m, 5H), 3.21 (s,2H), 3.06 (m, 1H), 2.73 (m, 3H), 2.25 (dd, J=12.6, 7.4 Hz, 3H),2.09-1.56 (m, 9H).

Example 7HH:(R)-(6-(4-(2-(2-methoxy-2-methylpropoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone

To a DMF (1 mL) solution of((R)-(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone)(20 mg, 0.054 mmol) and cesium carbonate (35.2 mg, 0.108 mmol), wasadded 1-bromo-2-methoxy-2-methylpropane (18.04 mg, 0.108 mmol). Theresulting mixture was stirred at 90° C. for 72 hr. The crude mixture wasdiluted with DCM (20 mL) and washed with water (2×20 mL). The organicswere dried over MgSO₄ and concentrated. The residue was purified bypreparative HPLC (XBridge 30×50 mm 35-60% MeCN/H₂O (5 mM NH₄OH)) toafford the title compound as a clear oil (2.8 mg, 0.006 mmol).

LCMS: Rt: 2.24 min (LCMS Method 3) MS m/z 457.4 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.23-7.10 (m, 2H), 6.98-6.87 (m, 2H),4.84-4.74 (m, 4H), 4.08-3.79 (m, 7H), 3.32 (s, 3H), 3.23-3.02 (m, 3H),2.71 (q, J=8.3 Hz, 1H), 2.20 (m, 3H), 2.06-1.54 (m, 9H), 1.35 (s, 6H).

Example 7H₁:(R)-oxetan-3-yl(6-(4-(2-((1-(trifluoromethyl)cyclopropyl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone

To a EtOH (1 mL) solution of((R)-(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone)(Intermediate 19A, 19 mg, 0.051 mmol) and potassium carbonate (14.18 mg,0.103 mmol) was added (1-(trifluoromethyl)cyclopropyl)methylbenzenesulfonate (13.43 mg, 0.062 mmol). The resulting mixture wasstirred at 90° C. for 72 hr. The crude mixture was diluted with DCM (20mL) and washed with water (2×20 mL). The organics were dried over MgSO₄and concentrated. The residue was purified by preparative HPLC (XBridge30×50 mm 35-60% MeCN/H₂O (5 mM NH₄OH)) to afford the title compound as awhite solid (15.5 mg, 0.031 mmol).

LCMS: Rt: 2.50 min (LCMS Method 4) MS m/z 493.2 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.24-7.12 (m, 2H), 6.98-6.85 (m, 2H),4.84-4.74 (m, 4H), 4.10 (s, 2H), 4.07-3.79 (m, 5H), 3.22-3.13 (m, 2H),3.07 (t, J=12.1 Hz, 1H), 2.77-2.62 (m, 1H), 2.17 (m, 3H), 1.95 (m, 5H),1.82-1.52 (m, 4H), 1.19-1.12 (m, 2H), 1.03-0.96 (m, 2H).

Example 7JJ:(R)-(6-(4-(2-(2,2-difluoroethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone

To an EtOH (1 mL) solution of((R)-(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone)(Intermediate 19A, 20 mg, 0.054 mmol) and potassium carbonate (14.92 mg,0.108 mmol) was added 2,2-difluoroethyl 4-methylbenzenesulfonate (15.3mg, 0.065 mmol). The resulting mixture was stirred at 80° C. for 72 hr.The crude mixture was diluted with DCM (20 mL) and washed with water(2×20 mL). The organics were dried over MgSO₄ and concentrated. Theresidue was purified by preparative HPLC (XBridge 30×50 mm 40-55%MeCN/H₂O (5 mM NH₄OH)) to afford the title compound as a clear oil (11.7mg, 0.027 mmol).

LCMS: Rt: 2.15 min (LCMS Method 4) MS m/z 435.4 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.27-7.14 (m, 2H), 7.05-6.91 (m, 2H), 6.22(tt, J=55.0, 3.7 Hz, 1H), 4.84-4.76 (m, 4H), 4.25 (m, 2H), 4.08-3.80 (m,5H), 3.21-3.10 (m, 2H), 3.03 (m, 1H), 2.71 (m, 1H), 2.27-2.09 (m, 3H),2.06-1.69 (m, 8H), 1.67-1.52 (m, 1H).

Example 7KK:(R)-oxetan-3-yl(6-(4-(2-(2-(oxetan-3-yl)ethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone

To an EtOH (1 mL) solution of((R)-(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone)(Intermediate 19A, 20 mg, 0.054 mmol) and potassium carbonate (14.92 mg,0.108 mmol) was added 2-(oxetan-3-yl)ethyl 4-methylbenzenesulfonate(16.6 mg, 0.065 mmol). The resulting mixture was stirred at 80° C. for48 hr. The crude mixture was diluted with DCM (20 mL) and washed withwater (2×20 mL). The organics were dried over MgSO₄ and concentrated.The residue was purified by preparative HPLC (XBridge 30×50 mm 25-40%MeCN/H₂O (5 mM NH₄OH)) to afford the title compound as a clear oil (11.7mg, 0.027 mmol).

LCMS: Rt: 2.13 min (LCMS Method 4) MS m/z 455.5 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.24-7.10 (m, 2H), 6.92 (t, J=7.8 Hz, 2H),4.84-4.76 (m, 4H), 4.07-3.78 (m, 10H), 3.72 (dd, J=8.6, 5.8 Hz, 1H),3.24-3.11 (m, 2H), 3.00 (t, J=12.0 Hz, 1H), 2.76 (m, 2H), 2.18 (m, 4H),2.07-1.68 (m, 9H), 1.67-1.51 (m, 1H).

Example 8A:(S)-(6-(4-(5-chloro-2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanoneor(R)-(6-(4-(5-chloro-2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanoneand Example 8B:(S)-(6-(4-(5-chloro-2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanoneor(R)-(6-(4-(5-chloro-2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone

1-fluorocyclopropanecarboxylic acid (114 mg, 1.098 mmol) was dissolvedin DMF (2 mL) and HATU (417 mg, 1.098 mmol) was added and the reactionwas stirred at RT for 20 min.6-(4-(5-chloro-2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 18B, 407 mg, 0.998 mmol), was dissolved in DCM (10 mL) andcooled to 0° C. and DIPEA (387 mg, 2.99 mmol) was added and the solutionwas concentrated. The residue was then dissolved in DMF (4 mL) and addedto the initial DMF solution. The reaction was stirred for 2 hr and itwas then quenched with water (50 mL). The aq layer was extracted withEtOAc (2×50 mL) and the combined organic layers were dried over MgSO₄,filtered and concentrated. The crude was purified by FCC (0-10% MeOH (1%NH₄OH)/DCM and the two enantiomers were then separated by chiralchromatography (IC 2×25 cm column, 60 mL/min, 30% MeOH/CO₂) to give thefaster eluting enantiomer Example 8A (52 mg, 0.117 mmol) and the slowerrunning enantiomer Example 8B (52 mg, 0.117 mmol).

Example 8A

SFC: Rt: 3.52 min (ID 4.6×100 mm, 5-55% MeOH (10 mM NH₄OH)/CO₂, 5mL/min) LCMS: Rt: 1.36 min (LCMS Method 3) MS m/z 421.0 [M+H]⁺.

¹H NMR (400 MHz,CD₃OD) δ 7.22-7.09 (m, 2H), 6.99-6.85 (m, 1H), 4.49-4.26(m, 2H), 4.05-3.86 (m, 2H), 3.83 (s, 3H), 3.23-3.11 (m, 2H), 2.98 (m,1H), 2.72 (d, J=9.2 Hz, 1H), 2.27 (m, 1H), 2.16 (q, J=10.5 Hz, 2H),2.08-1.50 (m, 9H), 1.35-1.20 (m, 4H).

Example 8B

SFC: Rt: 3.81 min (ID 4.6×100 mm, 5-55% MeOH (10 mM NH₄OH)/CO₂, 5mL/min)

LCMS: Rt: 1.36 min (LCMS Method 3) MS m/z 421.0 [M+H]⁺.

¹H NMR (400 MHz,CD₃OD) δ 7.22-7.09 (m, 2H), 6.99-6.85 (m, 1H), 4.49-4.26(m, 2H), 4.05-3.86 (m, 2H), 3.83 (s, 3H), 3.23-3.11 (m, 2H), 2.98 (tt,J=12.1, 3.8 Hz, 1H), 2.72 (d, J=9.2 Hz, 1H), 2.27 (dt, J=12.8, 6.4 Hz,1H), 2.16 (q, J=10.5 Hz, 2H), 2.08-1.50 (m, 9H), 1.35-1.20 (m, 4H).

Example 8C:(S)-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanoneor(R)-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanoneand Example 8D:(S)-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanoneor(R)-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone

6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 18C, 490 mg, 1.63 mmol), oxetane-3-carboxylic acid (183mg, 1.79 mmol), DIPEA (632 mg, 4.89 mmol) and TBTU (786 mg, 2.45 mmol)were reacted in a similar manner to Example 8A. The enantiomers werethen separated by chiral SFC (OJ-H, 2×25 cm, 10% MeOH (0.1% DEA)/CO₂, 75mL/min). Example 8C, the faster eluting enantiomer was isolated as awhite solid (89 mg, 1.63 mmol) and Example 8D, the slower elutingenantiomer was also isolated as a white solid (89 mg, 1.63 mmol).

Example 8C

SFC: Rt: 3.40 min (Chiralpak® IB 4.6×100 mm, 5 uM, 5-55% 1:1 MeOH/IPA(10 mM NH₄OH)/CO₂ 5 mL/min)

LCMS: Rt: 0.91 min (LCMS Method 3), MS m/z 385.2 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.14-7.21 (m, 2H) 6.87-6.96 (m, 2H) 4.76-4.83(m, 4H) 3.83-4.07 (m, 5H) 3.83 (s, 3H) 3.12-3.21 (m, 2H) 2.95-3.05 (m,1H) 2.67-2.78 (m, 1H) 2.10-2.28 (m, 3H) 1.87-2.06 (m, 3H) 1.73-1.87 (m,5H) 1.53-1.67 (m, 1H).

Example 8D

SFC: Rt: 3.55 min (Chiralpak® IB 4.6×100 mm, 5 uM, 5-55% 1:1 MeOH/IPA(10 mM NH₄OH)/CO₂ 5 mL/min)

LCMS: Rt: 0.92 min (LCMS Method 3), MS m/z 385.4 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.14-7.21 (m, 2H) 6.87-6.96 (m, 2H) 4.77-4.83(m, 4H) 3.83-4.07 (m, 5H) 3.83 (s, 3H) 3.11-3.21 (m, 2H) 2.94-3.05 (m,1H) 2.67-2.77 (m, 1H) 2.10-2.26 (m, 3H) 1.86-2.07 (m, 3H) 1.71-1.86 (m,5H) 1.54-1.67 (m, 1H).

Example 8E:(S)-(6-(4-(2-(difluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanoneor(R)-(6-(4-(2-(difluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanonecitrate salt and Example 8F:(S)-(6-(4-(2-(difluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanoneor(R)-(6-(4-(2-(difluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanonecitrate salt

6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 17D, 763 mg, 2.27 mmol), oxetane-3-carboxylic acid (255mg, 2.50 mmol), DIPEA (879 mg, 6.80 mmol) and TBTU (1092 mg, 3.40 mmol)were reacted in a similar manner to Example 8A. The enantiomers wereseparated by SFC (Chiralpak® IG 21×250 mm, 5 uM, 40% MeOH/CO₂, 80 g/min)to generate the faster eluting Example 8E (82 mg, 0.195 mmol) and theslower eluting Example 8F (81 mg, 0.193 mmol). Each compound wasindividually dissolved in MeOH (1 mL) and 0.5M citric acid (0.385 mL,0.193 mL) was added. The samples were then freeze dried to generate thetwo examples as citrate salts

Example 8E

SFC: Rt: 3.89 min (Chiralpak® IG 4.6×100 mm, 5 uM, 5-55% MeOH (10 mMNH₄OH)/CO₂, 5 mL/min)

LCMS: Rt: 1.05 min (LCMS Method 1), MS m/z 421.4 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.38 (m, 1H), 7.33-7.20 (m, 2H), 7.19-7.13 (m,1H), 6.87 (m, 1H), 4.82-4.73 (m, 4H), 4.19-3.78 (m, 5H), 3.63 (d, 3H),3.17-2.96 (m, 2H), 2.92-2.68 (m, 4H), 2.44 (m, 1H), 2.28-1.83 (m, 9H).One proton is obscured by the solvent peak.

Example 8F

SFC: Rt: 4.92 min (Chiralpak® IG 4.6×100 mm, 5 uM, 5-55% MeOH (10 mMNH₄OH)/CO₂, 5 mL/min)

LCMS: Rt: 2.10 min (LCMS Method 2), MS m/z 421.3 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.46-7.32 (m, 1H), 7.33-7.19 (m, 2H), 7.15 (d,1H), 6.87 (m, 1H), 4.78 (d, 4H), 4.26-3.75 (m, 5H), 3.63 (d, 3H), 3.07(s, 2H), 2.91-2.68 (m, 4H), 2.53-2.33 (m, 1H), 2.31-1.78 (m, 9H). Oneproton is obscured by the solvent peak.

Example 8G:(S)-oxetan-3-yl(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone

Oxetane-3-carboxylic acid (1.451 g, 14.21 mmol) was dissolved in DMF (40mL) and TBTU (4.56 g, 14.21 mmol) was added and the reaction was stirredat 50° C. for 20 minutes. Next,6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 18A, 3.65 g, 9.47 mmol) and DIPEA (6.62 mL, 37.9 mmol)dissolved in DCM (30 mL) were added to the reaction. The resultingmixture was stirred at RT for 16 hours. The solvent was thenconcentrated and the crude was purified by FCC (0-5% MeOH (1% 7N NH₃ inMeOH)/DCM) to yield racemic material (2.0 g, 4.56 mmol). This procedurewas then repeated on a second batch of6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 18A, 3.65 g, 9.47 mmol) to yield a second batch ofpurified racemic product (2.0 g, 4.56 mmol). The combined four grams ofracemic product were then purified by chiral SFC (Chiralpak® IG 21×250mm, 5 μM, 40% MeOH/CO₂, 80 g/min) to yield the two enantiomers Peak 1(1.079 g, 2.44 mmol) and Peak 2 (1.129 g, 2.55 mmol). Comparison of theretention time of the faster running enantiomer (Rt=2.22 min Chiralpak®IG-3 3×100 mm, 3 μM, 5-55% MeOH (0.1% NH₄OH)/CO₂, 2.5 mL/min) andExample 12A (Rt=2.22 min Chiralpak® IG-3 3×100 mm, 3 μM, 5-55% MeOH(0.1% NH₄OH)/CO₂, 2.5 mL/min) showed them to be equivalent. Therefore,the slower running enantiomer Example 8G (Rt=2.65 min Chiralpak® IG-33×100 mm, 3 μM, 5-55% MeOH (0.1% NH₄OH)/CO₂, 2.5 mL/min) is the (S)enantiomer.

Example 8G

SFC: Rt: 2.65 min (Chiralpak® IG-3 3×100 mm, 3 μM, 5-55% MeOH (0.1%NH₄OH)/CO₂, 2.5 mL/min).

LCMS: Rt: 2.37 min (LCMS Method 4), MS m/z 439.6 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.43 (d, J=7.6 Hz, 1H), 7.39-7.23 (m, 3H),4.84-4.75 (m, 4H), 4.10-3.80 (m, 5H), 3.24-3.13 (m, 2H), 2.98 (m, 1H),2.73 (q, J=7.5 Hz, 1H), 2.28-2.10 (m, 3H), 2.07-1.86 (m, 3H), 1.79 (ddd,J=15.6, 9.3, 4.3 Hz, 5H), 1.68-1.53 (m, 1H).

Example 9A:(R)-(1-fluorocyclopropyl)(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanoneor(S)-(1-fluorocyclopropyl)(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanoneand Example 9B:(R)-(1-fluorocyclopropyl)(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanoneor(S)-(1-fluorocyclopropyl)(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone

2-(1-fluorocyclopropanecarbonyl)-2-azaspiro[3.4]octan-6-one(Intermediate 2C, 280 mg, 1.326 mmol) and4-(2-(trifluoromethoxy)phenyl)piperidine (Intermediate 16A, 364 mg,1.484 mmol) were dissolved in DCM (7 mL) and AcOH (0.15 mL, 2.65 mmol)was added. The reaction mixture was stirred at room temperature for 1hour and then NaBH(OAc)₃ (421 mg, 1.988 mmol) was added and the reactionmixture was stirred at room temperature for 18 hours. The reactionmixture was neutralized with saturated aqueous sodium bicarbonate,extracted with DCM, dried over magnesium sulfate, filtered, andconcentrated. The crude residue was purified via FCC (0-100%EtOAc/heptanes; 0-25% MeOH/EtOAc; then 100% MeOH) and the enantiomerswere separated by chiral SFC (Chiralpak® IC 21×250 mm, 25% MeOH w/10 mMNH₄OH/CO₂ 80g/min). The faster eluting enantiomer afforded Example 9A(80 mg, 0.181 mmol) as an oil and the slower eluting enantiomer affordedExample 9B (80 mg, 0.181 mmol), also as an oil.

Example 9A

SFC RT: 2.55 min (ChiralPak® IC 4.6×100 mm, 5-55% MeOH w/10 mM NH₄OH/CO₂5 mL/min).

LCMS: RT: 2.88 min (LCMS Method 3) MS m/z 441.3 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 7.36 (d, J=6.85 Hz, 1H), 7.23 (m, 3H),4.44-4.21 (m, 2H), 3.90 (s, 2H), 3.19-3.05 (m, 2H), 3.02-2.88 (m, 1H),2.72-2.56 (m, 1H), 2.27-2.15 (m, 1H), 2.15-1.95 (m, 3H), 1.94-1.87 (m,1H), 1.80 (s, 5H), 1.37 (m, 2H), 1.29-1.08 (m, 4H).

Example 9B

SFC RT: 2.78 min (ChiralPak® IC 4.6×100 mm, 5-55% MeOH w/l0 mM NH₄OH/CO₂5 mL/min).

LCMS: RT: 2.87 min (LCMS Method 3) MS m/z 441.0 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 7.36 (d, J=7.4 Hz, 1H), 7.29-7.18 (m, 3H),4.41-4.20 (m, 2H), 4.05-3.91 (m, 1H), 3.89 (s, 1H), 3.11 (s, 2H), 2.93(s, 1H), 2.63 (s, 1H), 2.20 (s, 1H), 2.14-1.85 (m, 5H), 1.79 (s, 5H),1.35 (m, 2H), 1.30-1.11 (m, 3H).

Example 9C:(R)-(6-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanoneor(S)-(6-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanoneand Example 9D:(R)-(6-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanoneor(S)-(6-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone

To a solution of4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidinehydrochloride (Intermediate 16F, 200 mg, 0.716 mmol) in DCE (2 mL) wasadded DIPEA (246 mg, 1.90 mmol) and2-(1-fluorocyclopropane-1-carbonyl)-2-azaspiro[3.4]octan-6-one(Intermediate 2C, 200 mg, 0.947 mmol) followed by 4A molecular sieves(200 mg) and NaBH(OAc)₃ (671 mg, 3.17 mmol) at RT and stirred for 16 hr.The reaction mixture was diluted with DCM (5 mL) and filtered through aCelite pad, and the filtrate was washed with saturated solution ofNaHCO₃ (10 mL). The aqueous phase was extracted with DCM (2×5 mL), thecombined organic layers were dried by Na₂SO₄, filtered and concentrated.The crude was purified by preparative HPLC (XBridge C18 25×150 mm, 10μM, 5-95% MeCN/H₂O, 25 mL/min). The enantiomers were then separated bychiral SFC Chiralpak® IC 30×250 mm, 30% EtOH w/0.1% NH₄OH/CO₂ 34 mL/min)to yield peak 1 as Example 9C (51 mg, 0.11 mmol) and peak 2 as Example9D (52 mg, 0.11 mmol).

Example 9C

SFC RT: 1.53 min (ChiralPak® AD-3 4.6×50 mm, 5-40% EtOH w/0.05% DEA/CO₂₃ mL/min).

LCMS: RT: 1.08 min (LCMS Method 6) MS m/z 475.4 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 6.97-6.91 (m, 2H), 6.88-6.86 (m, 1H),4.54-4.51 (m, 1H), 4.36

-   -   4.30 (m, 2H), 3.99-3.88 (m, 4H), 3.62-3.57 (m, 2H), 3.20-3.17        (m, 2H), 3.07-3.01 (m, 1H), 2.77-2.73 (m, 1H), 2.28-2.16 (m,        3H), 2.04-2.00 (m, 5H), 1.83-1.60 (m, 8H), 1.28-1.23 (m, 4H).

Example 9D

SFC RT: 1.67 min (ChiralPak® AD-3 4.6×50 mm, 5-40% EtOH w/0.05% DEA/CO₂₃ mL/min).

LCMS: RT: 1.08 min (LCMS Method 6) MS m/z 475.4 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 6.97-6.91 (m, 2H), 6.87-6.85 (m, 1H),4.44-4.41 (m, 1H), 4.26-4.20 (m, 2H), 3.89-3.78 (m, 4H), 3.52-3.47 (m,2H), 3.09-3.06 (m, 2H), 2.96-2.90 (m, 1H), 2.67-2.57 (m, 1H), 2.17-2.16(m, 3H), 2.07-1.46 (m, 13H), 1.18-1.34 (m, 4H).

Example 9E:(R)-(1-fluorocyclopropyl)(6-(4-(2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanoneor(S)-(1-fluorocyclopropyl)(6-(4-(2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanoneand Example 9F:(R)-(1-fluorocyclopropyl)(6-(4-(2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanoneor(S)-(1-fluorocyclopropyl)(6-(4-(2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone

To a solution of 4-(2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidinehydrochloride (Intermediate 16G, 150 mg, 0.503 mmol) in DCE (1.5 mL) wasadded DIPEA (195 mg, 1.512 mmol) and2-(1-fluorocyclopropane-1-carbonyl)-2-azaspiro[3.4]octan-6-one(Intermediate 2C, 127 mg, 0.604 mmol) followed by 4A molecular sieves(150 mg) and NaBH(OAc)₃ (534 mg, 2.52 mmol) at 25° C. The reactionmixture was stirred for 16 hrs at 25° C. and it was then diluted withDCM (5 mL) and filtered through a Celite pad, and the filtrate waswashed with saturated solution of NaHCO₃ (5 mL). The aqueous phase wasextracted with DCM (2×5 mL), and the combined organic phases were driedwith Na₂SO₄, filtered and concentrated. The residue was then purified byPrep-HPLC (XBridge C18 25×150 mm, 10 μM, 5-95% MeCN/H₂O, 25 mL/min) andthe enantiomers were separated by chiral SFC (Chiralpak® AD 30×250 mm,30% EtOH w/0.1% NH₄OH/CO₂ 35 mL/min) to yield the initial peak asExample 9E (33 mg, 0.076 mmol) and the trailing peak as Example 9F (35mg, 0.076 mmol).

Example 9E

SFC RT: 1.52 min (ChiralPak® AD-3 4.6×50 mm, 5-40% EtOH w/0.05% DEA/CO₂₃ mL/min).

LCMS: RT: 1.05 min (LCMS Method 6) MS m/z 457.4 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.14-6.99 (m, 2H), 6.92-6.73 (m, 2H),4.51-4.49 (m, 2H), 4.39

-   -   4.12 (m, 2H), 3.99-3.72 (m, 4H), 3.54-3.52 (m, 2H), 3.09-3.06        (m, 2H), 2.97-2.90 (m, 1H), 2.72-2.53 (m, 1H), 2.19-2.15 (m,        1H), 2.11-2.00 (m, 2H), 1.98-1.87 (m, 4H), 1.78-1.60 (m, 7H),        1.55-1.44 (m, 1H), 1.19-1.12 (m, 4H), Example 9F SFC RT: 1.70        min (ChiralPak® AD-3 4.6×50 mm, 5-40% EtOH w/0.05% DEA/CO₂ ₃        mL/min).

LCMS: RT: 1.05 min (LCMS Method 6) MS m/z 457.4 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.25-7.11 (m, 2H), 7.02-6.88 (m, 2H),4.63-4.60 (m, 2H), 4.47

-   -   4.29 (m, 2H), 4.06-3.86 (m, 4H), 3.66-3.64 (m, 2H), 3.21-3.18        (m, 2H), 3.10-3.02 (m, 1H), 2.80-2.67 (m, 1H), 2.34-2.24 (m,        1H), 2.24-2.12 (m, 2H), 2.10-1.99 (m, 4H), 1.90-1.71 (m, 7H),        1.68-1.55 (m, 1H), 1.32-1.25 (m, 4H).

Example 9G:(R)-(1-fluorocyclopropyl)(6-(4-(2-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanoneor(S)-(1-fluorocyclopropyl)(6-(4-(2-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanoneand Example 9H:(R)-(1-fluorocyclopropyl)(6-(4-(2-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanoneor(S)-(1-fluorocyclopropyl)(6-(4-(2-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone

To a solution of 4-(2-(piperidin-4-yl)phenyl)tetrahydro-2H-pyran-4-olhydrochloride (Intermediate 16H, 600 mg, 2.01 mmol) in DCE (6 mL) was2-(1-fluorocyclopropane-1-carbonyl)-2-azaspiro[3.4]octan-6-one(Intermediate 2C, 234 mg, 1.11 mmol) followed by 4A molecular sieves(600 mg) and NaBH(OAc)₃ (1.17 g, 5.53 mmol) at 25° C. The reactionmixture was stirred for 16 hr at 25° C. The reaction mixture was dilutedwith DCM (10 mL), filtered and the filter cake was washed with DCM (2×5mL). The combined organic phases were washed with NaHCO₃ (10 mL), driedover Na₂SO₄, filtered and concentrated. The crude product was purifiedby FCC (0-50% MeOH/DCM) and enantiomers were then separated by chiralSFC (Chiralpak® AS-H 30×250 mm, 25% MeOH w/0.1% NH₄OH/CO₂ 50 g/min) togive Example 9G (37.54 mg, 0.08 mmol), the faster running enantiomer, asoff-white solid and Example 9H (52.4 mg, 0.11 mmol) the slower runningenantiomer as a white solid.

Example 9G

SFC: Rt: 1.455 min (Chiralpak® IC-3 4.6×50 mm, 40% MeOH (0.05% DEA)/CO₂₃ mL/min).

LCMS: Rt: 0.945 min (LCMS Method 6) MS m/z 457.4 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.42-7.35 (m, 2H), 7.25-7.20 (m, 1H),7.17-7.12 (m, 1H), 4.46-4.27 (m, 2H), 4.06-3.74 (m, 7H), 3.20-3.17 (m,2H), 2.86-2.71 (m, 1H), 2.31-2.13 (m, 5H), 2.06-1.97 (m, 3H), 1.96-1.76(m, 7H), 1.66-1.61 (m, 1H), 1.29-1.23 (m, 4H).

Example 9H

SFC: Rt: 2.001 min (Chiralpak® IC-3 4.6×50 mm, 40% MeOH (0.05% DEA)/CO₂₃ mL/min).

LCMS: Rt: 0.939 min (LCMS Method 6) MS m/z 457.3 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.42-7.36 (m, 2H), 7.26-7.21 (m, 1H),7.17-7.12 (m, 1H), 4.45-4.28 (m, 2H), 4.06-3.75 (m, 7H), 3.25-3.22 (m,2H), 2.88-2.84 (m, 1H), 2.33-2.15 (m, 5H), 2.07-1.86 (m, 10H), 1.71-1.62(m, 1H), 1.29-1.22 (m, 4H).

Example 9I:(R)-(6-(4-(5-fluoro-2-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanoneor(S)-(6-(4-(5-fluoro-2-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanoneand Example 9J:(R)-(6-(4-(5-fluoro-2-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanoneor(S)-(6-(4-(5-fluoro-2-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone

To a solution of4-(4-fluoro-2-(piperidin-4-yl)phenyl)tetrahydro-2H-pyran-4-olhydrochloride (Intermediate 161, 300 mg, 0.949 mmol) in DCE (3 mL) wasadded 2-(1-fluorocyclopropane-1-carbonyl)-2-azaspiro[3.4]octan-6-one(Intermediate 2C, 340 mg, 1.61 mmol) followed by 4A molecular sieves(300 mg) and NaBH(OAc)₃ (1133 mg, 5.35 mmol) at 25° C. The reactionmixture was stirred for 16 hr at 25° C. and it was then diluted with DCM(10 mL), filtered through a Celite pad, and the filtrate was washed withsaturated solution of NaHCO₃ (10 mL). The aqueous phase was extractedwith DCM (2×10 mL) and the combined organic phases were dried withNa₂SO₄, filtered and concentrated. The crude was purified by preparativeHPLC (XBridge 25×150 mm 5-95% MeCN/H₂O (10 mM NH₄HCO₃) 25 mL/min), andenantiomers were separated by chiral SFC (Chiralpak® AD-H 30×250 mm, 30%EtOH w/0.1% NH₄OH/CO₂ 60 g/min). The faster running enantiomer wasisolated as Example 9I (23 mg, 0.49 mmol) as a brown gum and the slowerrunning enantiomer was isolated as Example 9J (27 mg, 0.56 mmol) as abrown gum.

Example 9I

SFC: Rt: 1.406 min (Chiralpak® AD-3 4.6×50 mm, 5-40% EtOH (0.05%DEA)/CO₂ ₃ mL/min).

LCMS: Rt: 0.949 min (LCMS Method 6) MS m/z 475.4 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.45-7.41 (m, 1H), 7.12-7.08 (m, 1H),6.95-6.82 (m, 1H), 4.51-4.27 (m, 2H), 4.08-3.89 (m, 4H), 3.88-3.75 (m,3H), 3.26-3.14 (m, 2H), 2.95-2.67 (m, 1H), 2.34-2.12 (m, 5H), 2.08-1.79(m, 10H), 1.70-1.58 (m, 1H), 1.32-1.24 (m, 4H).

Example 9J

SFC: Rt: 1.490 min (Chiralpak® AD-3 4.6×50 mm, 5-40% EtOH (0.05%DEA)/CO₂ ₃ mL/min).

LCMS: Rt: 0.950 min (LCMS Method 6) MS m/z 475.4 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.45-7.43 (m, 1H), 7.12-7.08 (m, 1H),6.94-6.81 (m, 1H), 4.50-4.24 (m, 2H), 4.11-3.71 (m, 7H), 3.28-3.12 (m,2H), 2.92-2.71 (m, 1H), 2.36-2.10 (m, 5H), 2.09-1.78 (m, 10H), 1.71-1.55(m, 1H), 1.32-1.24 (m, 4H).

Example 9K:(R)-(6-(4-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanoneor(S)-(6-(4-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanoneand Example 9L:(R)-(6-(4-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanoneor(S)-(6-(4-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone

To a solution of4-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidinetrifluoroacetate (Intermediate 16J, 250 mg, 0.693 mmol) in DCE (3.0 mL)was added DIPEA (459 mg, 3.55 mmol) and2-(1-fluorocyclopropane-1-carbonyl)-2-azaspiro[3.4]octan-6-one(Intermediate 2C, 150 mg, 0.71 mmol) followed by 4A molecular sieves(150 mg) and NaBH(OAc)₃ (753 mg, 3.55 mmol) at 25° C. The reactionmixture was stirred for 16 hr at 25° C. The reaction mixture was dilutedwith DCM (5 mL) and filtered, the filter cake was washed with DCM (2×10mL). The combined organic phases were washed with NaHCO₃ (10 mL), driedwith Na₂SO₄, filtered and concentrated. The crude product was purifiedby preparative HPLC (XBridge 25×150 mm 5-95% MeCN/H₂O (0.05% mM NH₄HCO₃)25 mL/min) and further by preparative HPLC (XBridge 25×150 mm 5-95%MeCN/H₂O (10 mM NH₄OH) 25 mL/min), and enantiomers were separated bychiral SFC (Chiralpak® AD-H 30×250 mm, 30% EtOH w/0.1% NH₄OH/CO₂ 60g/min) to give the faster running enantiomer as Example 9K (44.46 mg,0.097 mmol) as a white solid and the slower running enantiomer asExample 9L (59.97 mg, 0.130 mmol) as a white solid.

Example 9K

SFC: Rt: 1.310 min (Chiralpak® AD-3 4.6×50 mm, 5-40% EtOH (0.05%DEA)/CO₂ ₃ mL/min).

LCMS: Rt: 1.006 min (LCMS Method 6) MS m/z 459.5 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.28-7.25 (m, 1H), 6.99-6.96 (m, 2H),4.32-4.31 (m, 2H), 4.05-4.02 (m, 4H), 3.99-3.90 (m, 2H), 3.88-3.56 (m,2H), 3.19-3.16 (m, 1H), 2.99-2.88 (m, 1H), 2.81-2.68 (m, 1H), 2.32-2.15(m, 3H), 1.84-1.80 (m, 3H), 1.80-1.79 (m, 7H), 1.64-1.60 (m, 3H),1.28-1.23 (m, 4H).

Example 9L

SFC: Rt: 1.418 min (Chiralpak® AD-3 4.6×50 mm, 5-40% EtOH (0.05%DEA)/CO₂ ₃ mL/min).

LCMS: Rt: 1.003 min (LCMS Method 6) MS m/z 459.5 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.29-7.25 (m, 1H), 6.99-6.96 (m, 2H),4.45-4.32 (m, 2H), 4.06-4.00 (m, 4H), 3.64-3.56 (m, 2H), 3.28-3.19 (m,2H), 3.16-3.03 (m, 1H), 3.01-2.92 (m, 1H), 2.83 (d, J=7.2 Hz, 1H),2.31-2.28 (m, 3H), 2.08-1.91 (m, 3H), 1.89-1.76 (m, 7H), 1.69-1.58 (m,3H), 1.28-1.23 (m, 4H).

Example 9M:(S)-(1-fluorocyclopropyl)(6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone

To a solution of 4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidinehydrochloride (Intermediate 16N, 150 mg, 0.539 mmol) in DCE (1.5 mL) wasadded DIPEA (205 mg, 1.59 mmol) and2-(1-fluorocyclopropane-1-carbonyl)-2-azaspiro[3.4]octan-6-one(Intermediate 2C, 112 mg, 0.53 mmol) followed by 4A molecular sieves(150 mg) and NaBH(OAc)₃ (562 mg, 2.65 mmol) at 25° C. The reactionmixture was stirred for 16 hr at 25° C. The reaction mixture was thendiluted with DCM (5 mL) and filtered through a Celite pad, and thefiltrate was washed with saturated solution of NaHCO₃ (10 mL), theaqueous phase was extracted with DCM (2×5 mL) and the combined organicphases were dried over Na₂SO₄, filtered and concentrated. The crude waspurified by preparative HPLC (XBridge 25×150 mm 5-95% MeCN/H₂O (0.05% mMNH₄HCO₃)), and enantiomers were separated by chiral SFC (Chiralpak® AD-34.6×50 mm, 5-40% EtOH w/0.05% DEA/CO₂ ₃ mL/min). Comparison of theretention time of the slower running enantiomer (Rt: 3.55 min Chiralpak®IC-3 3×100 mm, 3 μM 5-55% MeOH (0.1% NH₄OH)/CO₂ 3 mL/min) and Example 6E(Rt: 3.55 min Chiralpak® IC-3 3×100 mm, 3 M 5-55% MeOH (0.1% NH₄OH)/CO₂3 mL/min) showed them to be equivalent. Based on this, the fasterrunning enantiomer is the (50 mg, 0.11 mmol) is the title compound.

Example 9M

SFC: Rt: 3.27 min (Chiralpak® IC-3 3×100 mm, 3 M 5-55% MeOH (0.1%NH₄OH)/CO₂ ₃ mL/min)

LCMS: Rt: 0.989 min (LCMS Method 6) MS m/z 441.5 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.30-7.22 (m, 2H), 7.20-7.12 (m, 2H),4.47-4.27 (m, 2H), 4.11-3.87 (m, 4H), 3.63-3.57 (m, 2H), 3.23-3.06 (m,3H), 2.98-2.87 (m, 1H), 2.82-2.69 (m, 1H), 2.31-2.15 (m, 3H), 2.05-1.73(m, 10H), 1.70-1.55 (m, 3H), 1.31-1.21 (m, 4H) Example 10A:(R)-6-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-(5-fluoropyridin-3-yl)-2-azaspiro[3.4]octaneor(S)-6-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-(5-fluoropyridin-3-yl)-2-azaspiro[3.4]octaneand Example 10B:(R)-6-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-(5-fluoropyridin-3-yl)-2-azaspiro[3.4]octaneor(S)-6-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-(5-fluoropyridin-3-yl)-2-azaspiro[3.4]octane

To a solution of6-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 18G, 400 mg, 1.07 mmol) in toluene (4 mL) was added3-bromo-5-fluoropyridine (420 mg, 2.39 mmol), Cs₂CO₃ (1.56 g, 4.78 mmol)and RuPhos Pd G2 (124 mg, 0.16 mmol) at 25° C. and then N₂ was blowninto the vial for 1 minute. The reaction was stirred at 120° C. for 2hr. The reaction mixture was quenched with H₂O (10 mL) and extractedwith EtOAc (3×5 mL), washed with saturation solution of NaCl (10 mL),dried over Na₂SO₄, filtered and concentrated. The crude product waspurified by FCC (0-50% MeOH/DCM) and further purified by preparativeHPLC (XBridge 25×150 mm 5-95% MeCN/H₂O (0.05% mM NH₄HCO₃)). Theenantiomers were then separated by chiral SFC (Chiralpak® AD 30×250 mm,50% EtOH w/0.1% NH₄OH/CO₂ ₇₀ g/min) to give the faster runningenantiomer as Example 10A (58.95 mg, 0.12 mmol) as a yellow solid andthe slower running enantiomer as Example 10B (61.56 mg, 0.13 mmol) as ayellow solid.

Example 10A

SFC: Rt: 2.111 min (Chiralpak® AD-3 4.6×50 mm, 5-40% EtOH (0.05%DEA)/CO₂ ₃ mL/min).

LCMS: Rt: 1.132 min (LCMS Method 6) MS m/z 484.4 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.72 (d, J=2.4 Hz, 1H), 7.58-7.57 (m, 1H),6.96-6.94 (m, 2H), 6.93-6.91 (m, 1H), 6.85-6.63 (m, 1H), 4.53-4.49 (m,1H), 3.94-3.90 (m, 4H), 3.81-3.75 (m, 2H), 3.59-3.18 (m, 2H), 3.18 (t,J=9.8 Hz, 2H), 3.03 (br s, 1H), 2.75 (t, J=8.0 Hz, 1H), 2.28-2.16 (m,1H), 2.23-2.12 (m, 2H), 2.08-1.92 (m, 5H), 1.91-1.79 (m, 3H), 1.74-1.67(m, 5H) Example 10B

SFC: Rt: 2.146 min (Chiralpak® AD-3 4.6×50 mm, 5-40% EtOH (0.05%DEA)/CO₂ ₃ mL/min).

LCMS: Rt: 1.155 min (LCMS Method 6) MS m/z 484.4 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.73 (d, J=2.4 Hz, 1H), 7.64-7.55 (m, 1H),7.00-6.91 (m, 2H), 6.89-6.82 (m, 1H), 6.67-6.64 (m, 1H), 4.53-4.52 (m,1H), 3.93-3.91 (m, 4H), 3.87-3.78 (m, 2H), 3.62-3.19 (m, 2H), 3.16-3.13(m, 2H), 3.12-2.97 (m, 1H), 2.83-2.69 (m, 1H), 2.29-2.04 (m, 1H), 2.17(d, J=9.8 Hz, 2H), 2.09-1.94 (m, 5H), 1.89-1.78 (m, 3H), 1.75-1.69 (m,5H).

Example 10C:(R)-6-(4-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octaneor(S)-6-(4-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octaneand Example 10D:(R)-6-(4-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octaneor(S)-6-(4-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane

To the solution of6-(4-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 18E, 400 mg, 1.075 mmol) in toluene (4 mL) was addedCs₂CO₃ (1.9 g, 4.28 mmol), 5-bromopyrimidine (853 mg, 5.37 mmol) andRuPhos Pd G2 (78 mg, 0.11 mmol). The reaction mixture was stirred for 2hr at 110° C. under N₂. The reaction mixture was then diluted with H₂O(5 mL), and extracted with EtOAc (3×5 mL). The combined organic phaseswere dried over Na₂SO₄, filtered and concentrated. The residue waspurified by FCC (0-30% MeOH/DCM) and the material was further purifiedby preparative HPLC (XBridge 25×150 mm 5-95% MeCN/H₂O (0.05% mMNH₄HCO₃). The enantiomers were then separated by chiral SFC (Chiralpak®AS 30×250 mm, 30% IPA w/0.1% NH₄OH/CO₂ ₆₀ g/min) to give the fasterrunning enantiomer as Example 10C (89.77 mg, 0.078 mmol) as a whitesolid and the slower running enantiomer as Example 10D (94.67 mg, 0.210mmol) as a white solid.

Example 10C

SFC: Rt: 2.013 min (Chiralpak® AD-3 4.6×50 mm, 5-40% EtOH (0.05%DEA)/CO₂ ₃ mL/min).

LCMS: Rt: 0.989 min (LCMS Method 6) MS m/z 451.4 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.48 (s, 1H), 8.01 (s, 2H), 7.29-7.25 (m, 1H),7.00-6.96 (m, 1H), 6.90-6.89 (m, 1H), 4.06-4.02 (m, 2H), 3.94-3.92 (m,2H), 3.87-3.85 (m, 2H), 3.62-3.59 (m, 2H), 3.23-3.15 (m, 2H), 3.12-3.04(m, 1H), 2.99-2.89 (m, 1H), 2.84-2.72 (m, 1H), 2.34-2.18 (m, 3H),2.09-1.95 (m, 3H), 1.87-1.75 (m, 7H), 1.64-1.61 (m, 3H).

Example 10D

SFC: Rt: 1.902 min (Chiralpak® AD-3 4.6×50 mm, 5-40% EtOH (0.05%DEA)/CO₂ ₃ mL/min).

LCMS: Rt: 0.993 min (LCMS Method 6) MS m/z 451.4 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.48 (s, 1H), 8.01 (s, 2H), 7.29-7.25 (m, 1H),7.00-6.96 (m, 1H), 6.90-6.89 (m, 1H), 4.05-4.02 (m, 2H), 3.96-3.90 (m,2H), 3.89-3.83 (m, 2H), 3.63-3.56 (m, 2H), 3.22-3.17 (m, 2H), 3.12-3.04(m, 1H), 3.00-2.88 (m, 1H), 2.83-2.75 (m, 1H), 2.34-2.19 (m, 3H),2.10-1.96 (m, 3H), 1.87-1.76 (m, 7H), 1.64-1.61 (m, 3H).

Example 10E:(R)-6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octaneor(S)-6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octaneand Example 10F:(R)-6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octaneor(S)-6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane

To a solution of6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 18F, 100 mg, 0.209 mmol) in toluene (1 mL) was added5-bromopyrimidine (198 mg, 1.25 mmol), Cs₂CO₃ (407 mg, 1.25 mmol) andRuPhos Pd G2 (23 mg, 0.03 mmol). The reaction mixture was stirred for 2hr at 110° C. under N₂ and the reaction mixture was diluted with H₂O (3mL), and then extracted with EtOAc (3×5 mL). The combined organic phaseswere dried over Na₂SO₄, filtered and concentrated and the crude waspurified by FCC (0-20% MeOH/DCM). The material was further purified bypreparative HPLC (XBridge 25×150 mm 5-95% MeCN/H₂O (0.05% mM NH₄HCO₃))and the enantiomers were separated by chiral SFC (Chiralpak® AS 30×250mm, 35% IPA w/0.1% NH₄OH/CO₂ ₆₀ g/min) to give the faster runningenantiomer as Example 10E (3.45 mg, 0.007 mmol) as a brown gum and theslower running enantiomer as Example 10F (6.94 mg, 0.014 mmol) as abrown gum.

Example 10E

SFC: Rt: 1.674 min (Chiralpak® AS-3 4.6×50 mm, 5-40% IPA (0.05% DEA)/CO₂₃ mL/min).

LCMS: Rt: 1.014 min (LCMS Method 6) MS m/z 479.4 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.50 (s, 1H), 8.03 (s, 2H), 6.95-6.92 (m, 1H),6.89-6.81 (m, 1H), 6.75-6.72 (m, 1H), 4.78 (s, 2H), 4.70 (s, 2H),4.59-4.52 (m, 1H), 3.98-3.92 (m, 2H), 3.91-3.85 (m, 2H), 3.24-3.16 (m,2H), 3.00-2.93 (m, 1H), 2.86-2.75 (m, 3H), 2.35-2.30 (m, 3H), 2.25-2.14(m, 2H), 2.10-1.97 (m, 3H), 1.88-1.81 (m, 3H), 1.77-1.62 (m, 3H)

Example 10F

SFC: Rt: 1.842 min (Chiralpak® AS-3 4.6×50 mm, 5-40% IPA (0.05% DEA)/CO₂₃ mL/min).

LCMS: Rt: 1.028 min (LCMS Method 6) MS m/z 479.4 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.50 (s, 1H), 8.03 (s, 2H), 6.95-6.92 (m, 1H),6.88-6.82 (m, 1H), 6.75-6.71 (m, 1H), 4.78 (s, 2H), 4.70 (s, 2H),4.57-4.54 (m, 1H), 3.98-3.92 (m, 2H), 3.90-3.85 (m, 2H), 3.23-3.15 (m,2H), 2.99-2.93 (m, 1H), 2.86-2.80 (m, 2H), 2.78-2.71 (m, 1H), 2.35-2.29(m, 3H), 2.20-2.13 (m, 2H), 2.09-1.97 (m, 3H), 1.87-1.81 (m, 3H),1.76-1.61 (m, 3H).

Example 10G:(R)-6-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octaneor(S)-6-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octaneand Example 10H:(R)-6-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octaneor(S)-6-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane

To a solution of6-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 18G, 150 mg, 0.386 mmol) in toluene (1.5 mL) was addedCs₂CO₃ (629 mg, 1.93 mmol), 5-bromopyrimidine (184 mg, 1.16 mmol) andRuPhos Pd G2 (30 mg, 0.039 mmol). The reaction mixture was stirred for 2hr at 120° C. under N₂ and then the reaction mixture was diluted withH₂O (3 mL), and extracted with EtOAc (3×5 mL). The combined organicphases were dried over Na₂SO₄, filtered, concentrated and purified byprep TLC (DCM: MeOH: 10:1 w/0.1% NH₄OH). The material was furtherpurified by preparative HPLC (XBridge 25×150 mm 5-95% MeCN/H₂O (0.05%NH₄HCO₃)), and enantiomers were separated by chiral SFC (Chiralpak® AS30×250 mm, 30% IPA w/0.1% NH₄OH/CO₂ ₆₀ g/min) to give the faster runningenantiomer as Example 10G (19.8 mg, 0.042 mmol) as a yellow solid andthe slower running enantiomer as Example 10H (22.15 mg, 0.047 mmol) as ayellow gum.

Example 10G

SFC: Rt: 1.639 min (Chiralpak® AS-3 4.6×50 mm, 5-40% IPA (0.05% DEA)/CO₂₃ mL/min).

LCMS: Rt: 1.057 min (LCMS Method 6) MS m/z 467.4 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.48 (s, 1H), 8.01 (s, 2H), 6.98-6.93 (m, 2H),6.92-6.86 (m, 1H), 4.55-4.49 (m, 1H), 3.96-3.91 (m, 4H), 3.86-3.85 (m,2H), 3.63-3.57 (m, 2H), 3.26-3.24 (m, 2H), 3.09-3.03 (m, 1H), 2.86-2.79(m, 1H), 2.36-2.29 (m, 3H), 2.29-2.00 (m, 5H), 1.88-1.87 (m, 3H),1.75-1.60 (m, 5H)

Example 10H

SFC: Rt: 1.752 min (Chiralpak® AS-3 4.6×50 mm, 5-40% IPA (0.05% DEA)/CO₂₃ mL/min).

LCMS: Rt: 0.867 min (LCMS Method 6) MS m/z 467.4 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.48 (s, 1H), 8.01 (s, 2H), 6.98-6.92 (m, 2H),6.87-6.86 (m, 1H), 4.55-4.51 (m, 1H), 3.96-3.94 (m, 4H), 3.92-3.90 (m,2H), 3.63-3.57 (m, 2H), 3.21-3.19 (m, 2H), 3.10-3.00 (m, 1H), 2.80-2.76(m, 1H), 2.34-2.31 (m, 1H), 2.29-2.17 (m, 2H), 2.05-1.84 (m, 8H),1.75-1.62 (m, 5H).

Example 101:S)-2-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)oxazoleor(R)-2-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)oxazoleand Example 10J(S)-2-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)oxazoleor(R)-2-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)oxazole

6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 18C, 111 mg, 0.369 mmol), 2-bromooxazole (0.066 g, 0.443mmol), Pd(dba)₂ (21 mg, 0.037 mmol), xantphos (26 mg, 0.044 mmol), andNaOtBu (71 mg, 0.739 mmol) were dissolved in dioxane (4 mL). Thereaction was stirred for 16 hours at 75° C. and it was then filtered andthe filtrate was concentrated and purified by FCC (0-25% MeOH(10%NH₄OH)/EtOAc) to give the racemic title compound. The enantiomers werethen separated by chiral SFC (Chiralcel OD-H 21×250 mm column, 80 g/minflow rate, 35% IPA (10 mM NH₄OH)/CO₂). The faster running enantiomer wasisolated as Example 101 (51 mg, 0.137 mmol) and the slower runningenantiomer was isolated as Example 10J (42 mg, 0.111 mmol).

Example 101

SFC: Rt: 3.57 min (Chiralcel© OD-H 4.6×100 mm, 5-55% IPA (10 mMNH₄OH)/CO₂, 5 mL/min).

LCMS: Rt: 0.93 min (LCMS Method 3), MS m/z 368.6 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.37 (d, J=1.4 Hz, 1H), 7.15 (t, J=7.6 Hz,2H), 6.95-6.84 (m, 2H), 6.80 (d, J=1.3 Hz, 1H), 4.08-3.88 (m, 4H), 3.81(s, 3H), 3.21-3.10 (m, 2H), 3.05-2.91 (m, 1H), 2.70 (d, J=8.3 Hz, 1H),2.27 (dd, J=12.9, 7.3 Hz, 1H), 2.22-2.08 (m, 2H), 2.08-1.86 (m, 3H),1.86-1.68 (m, 5H), 1.59 (d, J=3.5 Hz, 1H).

Example 10J

SFC: Rt: 4.18 min (Chiralcel© OD-H 4.6×100 mm, 5-55% IPA (10 mMNH₄OH)/CO₂, 5 mL/min).

LCMS: Rt: 0.89 min (LCMS Method 3), MS m/z 368.3 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.37 (d, J=1.4 Hz, 1H), 7.20-7.10 (m, 2H),6.95-6.85 (m, 2H), 6.80 (d, J=1.4 Hz, 1H), 4.07-3.88 (m, 4H), 3.81 (s,3H), 3.20-3.10 (m, 2H), 3.04-2.90 (m, 1H), 2.77-2.63 (m, 1H), 2.27 (dd,J=12.9, 7.3 Hz, 1H), 2.21-2.08 (m, 2H), 2.08-1.88 (m, 3H), 1.85-1.67 (m,5H), 1.67-1.48 (m, 1H).

Example 10K:(R)-2-(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)oxazoleor(S)-2-(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)oxazoleand Example 10L:(R)-2-(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)oxazoleor(S)-2-(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)oxazole

6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 18A, 166 mg, 0.468 mmol) was added to a vial followed by asolution of 2-bromooxazole (83 mg, 0.562 mmol) in dioxane (4.7 mL) andthis was placed under nitrogen. Pd(dba)₂ (26.9 mg, 0.047 mmol), xantphos(32.5 mg, 0.056 mmol) and NaOtBu (90 mg, 0.937 mmol) were added and thiswas heated to 75° C. for 16 hr. The reaction was cooled to roomtemperature, filtered, and rinsed through with MeCN and EtOAc. Thefiltrate was evaporated and the residue was then purified by FCC (0-10%MeOH (1% NH₄OH)/DCM). The purified racemic material was then separatedby chiral SFC (Chiralpak® IG 21×250 mm column, 80 g/min flow rate, 18%MeOH (10 mM NH₄OH)/CO₂). The faster running enantiomer was isolated asExample 10K (19 mg, 0.043 mmol) and the slower running enantiomer wasisolated as Example 10L (19 mg, 0.043 mmol).

Example 10K

SFC: Rt: 2.55 min (Chiralpak® ID 4.6×100 mm, 5-55% MeOH (10 mMNH₄OH)/CO₂, 5 mL/min).

LCMS: Rt: 2.88 min (LCMS Method 4), MS m/z 422.3 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.42 (dd, J=7.5, 1.8 Hz, 1H), 7.37 (d, J=1.3Hz, 1H), 7.37-7.22 (m, 3H), 6.80 (d, J=1.4 Hz, 1H), 4.06-3.88 (m, 4H),3.18 (d, J=11.5 Hz, 2H), 3.04-2.91 (m, 1H), 2.81-2.66 (m, 1H), 2.28 (dd,J=13.0, 7.3 Hz, 1H), 2.16 (s, 2H), 2.09-1.89 (m, 3H), 1.79 (m, 5H),1.67-1.51 (m, 1H).

Example 10L

SFC: Rt: 2.69 min (Chiralpak® ID 4.6×100 mm, 5-55% MeOH (10 mMNH₄OH)/CO₂, 5 mL/min).

LCMS: Rt: 2.84 min (LCMS Method 4), MS m/z 422.3 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.42 (dd, J=7.7, 1.8 Hz, 1H), 7.38 (d, J=1.0Hz, 1H), 7.36-7.22 (m, 3H), 6.80 (s, 1H), 4.08-3.89 (m, 4H), 3.18 (d,J=11.3 Hz, 2H), 2.97 (p, J=8.5 Hz, 1H), 2.81-2.67 (m, 1H), 2.28 (dd,J=12.8, 7.3 Hz, 1H), 2.16 (s, 2H), 2.08-1.89 (m, 3H), 1.80 (m, 5H), 1.59(m, 1H).

Example 10M:(R)-2-(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazoleor(S)-2-(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazoleand Example 10N:(R)-2-(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazoleor(S)-2-(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole

To the solution of6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 18A, 300 mg, 0.846 mmol) in 2% aqueous TPGS-750-M (1.5 mL)and THE (0.15 mL) was added 2-bromo-1,3,4-thiadiazole (140 mg, 0.846mmol), followed by K₃PO₄ (180 mg, 0.846 mmol). The mixture was stirredunder N₂ for 16 hr and then the reaction was extracted with DCM. The DCMwas concentrated and the crude was purified by FCC (0-7% MeOH/DCM). Theracemic material was then separated by chiral SFC (Chiralpak® IG 21×250mm column, 80 mL/min flow rate, 30% MeOH (10 mM NH₄OH)/CO₂) to give thefaster running enantiomer as Example 10M (72 mg, 0.161 mmol) and theslower running enantiomer as Example 10N (78 mg, 0.174 mmol).

Example 10M

SFC: Rt: 3.15 min (Chiralpak® IG 4.6×100 mm, 5-55% MeOH (10 mMNH₄OH)/CO₂, 5 mL/min).

LCMS: Rt: 1.27 min (LCMS Method 3), MS m/z 439.1 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) δ 8.78 (s, 1H), 7.51-7.45 (m, 1H), 7.40-7.27(m, 3H), 4.02-3.84 (m, 4H), 3.10-2.97 (m, 2H), 2.87-2.72 (m, 1H),2.70-2.57 (m, 1H), 2.20-2.10 (m, 1H), 2.05-1.92 (m, 3H), 1.92-1.78 (m,2H), 1.78-1.60 (m, 5H), 1.57-1.42 (m, 1H).

Example 10N

SFC: Rt: 3.46 min (Chiralpak® IG 4.6×100 mm, 5-55% MeOH (10 mMNH₄OH)/CO₂, 5 mL/min).

LCMS: Rt: 1.28 min (LCMS Method 3), MS m/z 439.3 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) δ 8.78 (s, 1H), 7.53-7.44 (m, 1H), 7.41-7.26(m, 3H), 4.04-3.84 (m, 4H), 3.11-2.96 (m, 2H), 2.88-2.74 (m, 1H),2.70-2.59 (m, 1H), 2.15 (dd, J=12.7, 6.8 Hz, 1H), 2.05-1.78 (m, 5H),1.77-1.60 (m, 5H), 1.58-1.41 (m, 1H).

Example 10O:(R)-2-(6-(4-(2-(difluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazoleor(S)-2-(6-(4-(2-(difluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazoleand Example 10P:(R)-2-(6-(4-(2-(difluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazoleor(S)-2-(6-(4-(2-(difluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole

6-(4-(2-(difluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Example 18D, 120 mg, 0.357 mmol) was added to a vial followed by asolution of 2-bromooxazole (63.3 mg, 0.428 mmol) in dioxane (3.5 mL) andthis was placed under nitrogen. Pd(dba)₂ (20.51 mg, 0.036 mmol),xantphos (24.77 mg, 0.043 mmol) and NaOtBu (68.6 mg, 0.713 mmol) wereadded and this was heated to 75° C. The reaction was stirred for 16 hrand then it was filtered, rinsed with EtOAc and concentrated. Theresidue was then purified by FCC (0-10% MeOH (10% NH₄OH)/DCM to yieldthe racemic product. The enantiomers were then separated by chiral SFC(Chiralpak® AD-H 21×250 mm column, 80 g/min flow rate, 20% MeOH (1%isopropylamine)/CO₂) to give the faster running enantiomer as Example10O (13 mg, 0.03 mmol) and the slower running enantiomer as Example 10P(16 mg, 0.038 mmol).

Example 10O

SFC: Rt: 3.11 min (Chiralpak® IG 4.6×100 mm, 5-55% MeOH (10 mMNH₄OH)/CO₂, 5 mL/min).

LCMS: Rt: 2.55 min (LCMS Method 3), MS m/z 404.3 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.46-7.35 (m, 2H), 7.35-7.23 (m, 2H), 7.16 (t,J=7.8 Hz, 1H), 6.85 (d, J=9.2 Hz, 1H), 4.13-3.92 (m, 4H), 3.24 (s, 2H),3.07 (d, J=10.6 Hz, 1H), 2.79 (d, J=9.8 Hz, 1H), 2.34 (dd, J=13.0, 7.5Hz, 1H), 2.27 (d, J=22.3 Hz, 2H), 2.17-1.92 (m, 3H), 1.92-1.77 (m, 6H),1.73-1.58 (m, 1H).

Example 10P

SFC: Rt: 3.40 min (Chiralpak® IG 4.6×100 mm, 5-55% MeOH (10 mMNH₄OH)/CO₂, 5 mL/min).

LCMS: Rt: 2.52 min (LCMS Method 3), MS m/z 404.3 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.28 (d, J=1.4 Hz, 1H), 7.24 (dd, J=7.2, 2.2Hz, 1H), 7.13 (m, 2H), 7.06-6.99 (m, 1H), 6.71 (d, J=2.2 Hz, 1H),4.00-3.75 (m, 4H), 3.14 (s, 2H), 2.94 (dt, J=11.3, 6.7 Hz, 1H), 2.72 (s,1H), 2.21 (dd, J=12.9, 7.5 Hz, 3H), 1.98-1.82 (m, 3H), 1.72 (m, 6H),1.56-1.46 (m, 1H).

Example 10Q:(R)-5-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,2,4-thiadiazoleor(S)-5-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,2,4-thiadiazoleand Example 10R:(R)-5-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,2,4-thiadiazoleor(S)-5-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,2,4-thiadiazole

Into a vial was added6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 18C, 0.055 g, 0.183 mmol) followed by a solution of5-bromo-1,2,4-thiadiazole (0.036 g, 0.220 mmol) in dioxane (1.8 mL) andthis was placed under nitrogen. A white precipitate formed and tenminutes later, additional 5-bromo-1,2,4-thiadiazole (0.018 g, 0.11 mmol)in dioxane (0.5 mL) was added and the reaction was sonicated. Thereaction was stirred for 72 hours and then it was diluted with saturatedaqueous sodium bicarbonate and EtOAc, extracted with EtOAc (2×), driedwith MgSO₄, filtered and concentrated. The residue was purified by FCC(0-15% MeOH (10% NH₄OH/EtOAc) to give the purified racemate. Theenantiomers were then separated by chiral SFC (Chiralpak® AD-H 21×250 mmcolumn, 80 g/min flow rate, 30% MeOH (1% isopropylamine)/CO₂) to givethe faster running enantiomer as Example 10Q (9 mg, 0.023 mmol) and theslower running enantiomer as Example 10R (9 mg, 0.023 mmol).

Example 10Q

SFC: Rt: 3.14 min (Chiralpak® IG 4.6×100 mm, 5-55% MeOH (10 mMNH₄OH)/CO₂, 5 mL/min).

LCMS: Rt: 1.15 min (LCMS Method 3), MS m/z 385.2 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.92 (s, 1H), 7.20-7.11 (m, 2H), 6.95-6.85 (m,2H), 4.17-3.96 (m, 4H), 3.81 (s, 3H), 3.22-3.10 (m, 2H), 3.05-2.91 (m,1H), 2.84-2.65 (m, 1H), 2.32 (dd, J=12.9, 7.3 Hz, 1H), 2.26-1.92 (m,5H), 1.92-1.69 (m, 5H), 1.69-1.52 (m, 1H).

Example 10R

SFC: Rt: 3.60 min (Chiralpak® IG 4.6×100 mm, 5-55% MeOH (10 mMNH₄OH)/CO₂, 5 mL/min).

LCMS: Rt: 1.13 min (LCMS Method 3), MS m/z 385.3 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.92 (s, 1H), 7.21-7.08 (m, 2H), 6.98-6.82 (m,2H), 4.17-3.95 (m, 4H), 3.81 (s, 3H), 3.23-3.08 (m, 2H), 3.07-2.92 (m,1H), 2.86-2.64 (m, 1H), 2.32 (dd, J=13.0, 7.4 Hz, 1H), 2.25-1.92 (m,5H), 1.92-1.70 (m, 5H), 1.70-1.50 (m, 1H).

Example 10T:(S)-2-(6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole

To a THF (7 mL) solution of6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane(Intermediate 18H, 490 mg, 1.313 mmol) and ethyl5-bromo-1,3,4-oxadiazole-2-carboxylate (348 mg, 1.576 mmol) were cooledto 0° C. and DIEA (0.55 mL, 3.15 mmol) was added. The reaction wasstirred for 2 h at RT and then the reaction mixture was concentratedunder vacuum and diluted with DCM. The crude organic was washed withwater and brine then dried over sodium sulfate, filtered andconcentrated. The residue was dissolved in THE (4 mL) and LiOH (331 mg,7.88 mmol) in water (3 mL) was added. The reaction was stirred for 16 hand then it was cooled to 0° C. and 6N HCl (2.2 mL, 13.13 mmol) wasadded and the reaction was stirred for 2 h. Next, solid sodium carbonatewas added until the was pH >12 and then the reaction was concentrated.The residue was dissolved in EtOAc and the organic layer was washed withbrine, dried over sodium sulfate and concentrated. The crude was thenpurified by FCC (0-10% 7N NH₃ in MeOH/40% EtOAc/heptanes) to yield theracemate (284 mg, 0.672 mmol). 262 mg of this material was thensubjected to chiral SFC to separate the enantiomers (Chiralpak® IG-321×250 mm column, 80 g/min flow rate, 30% MeOH (1% isopropylamine)/CO₂Comparison of the SFC retention time of Example 2H (Rt: 1.92 min;Chiralpak® OJ-3 3 μM, 3×100 mm, 5-55% IPA (0.1% NH₄OH)/CO₂, 2.5 mL/min)shows that the trailing peak from this separation (Rt: 1.92 min;Chiralpak® OJ-3 3 μM, 3×100 mm, 5-55% IPA (0.1% NH₄OH)/CO₂, 2.5 mL/min)is equivalent to Example 2H. Therefore, the faster running enantiomerfrom this separation is title compound (91 mg, 0.213 mmol).

SFC: Rt: 1.73 min (Rt: 1.92 min; Chiralpak® OJ-3 3 μM, 3×100 mm, 5-55%IPA (0.1% NH₄OH)/CO₂, 2.5 mL/min)

LCMS: Rt: 2.14 min (LCMS Method 3), MS m/z 423.4 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.36 (s, 1H), 7.27-7.24 (m, 2H), 7.21-7.12 (m,2H), 4.13 (d, J=7.8 Hz, 1H), 4.09-3.97 (m, 5H), 3.60 (td, J=11.8, 2.0Hz, 2H), 3.23-3.06 (m, 3H), 2.92 (tt, J=11.8, 4.0 Hz, 1H), 2.83-2.69 (m,1H), 2.31 (dd, J=13.1, 7.3 Hz, 1H), 2.24-2.17 (m, 2H), 2.12-1.91 (m,3H), 1.91-1.70 (m, 7H), 1.70-1.55 (m, 3H).

Example 11A:(R)-(6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanoneor(S)-(6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanoneand Example 11B:(R)-(6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanoneor(S)-(6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone

To a solution of(6-(4-(5-fluoro-2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone(Intermediate 171, 500 mg, 1.02 mmol) in DMF (5 mL) was added2-oxaspiro[3.3]heptan-6-yl 4-methylbenzenesulfonate (Intermediate 7A,410 mg, 1.53 mmol) and Cs₂CO₃ (995 mg, 3.05 mmol) at 25° C. The reactionwas stirred at 25° C. for 16 hr. The reaction mixture was filtered andfilter cake was washed with MeOH (1 mL). The filtrate was purified bypreparative HPLC (XBridge 25×150 mm 5-95% MeCN/H₂O (0.05% NH₄OH)) andthe enantiomers were then purified by chiral SFC (Chiralpak® IC 30×250mm column, 60 g/min flow rate, 70% MeOH (0.1% NH₄OH)/CO₂) to yield thefaster running enantiomer as Example 11A (74 mg, 0.15 mmol) and theslower running enantiomer as Example 11B (69 mg, 0.14 mmol).

Example 11A

SFC: Rt: 2.148 min (Chiralpak® IC-3 4.6×50 mm, 40% EtOH (0.05% DEA)/CO₂₃ mL/min).

LCMS: Rt: 0.995 min (LCMS Method 6) MS m/z 487.5 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 6.91-6.90 (m, 1H), 6.89-6.82 (m, 1H),6.72-6.69 (m, 1H), 4.75 (s, 2H), 4.67 (s, 2H), 4.53 (t, J=6.4 Hz, 1H),4.51-4.32 (m, 2H), 4.31-3.29 (m, 2H), 4.01-3.99 (m, 2H), 3.00-2.89 (m,1H), 2.86-2.69 (m, 3H), 2.32-2.29 (m, 5H), 2.28-2.16 (m, 3H), 2.01-1.93(m, 6H), 1.28-1.23 (m, 4H).

Example 11B

SFC: Rt: 2.875 min (Chiralpak® IC-3 4.6×50 mm, 40% EtOH (0.05% DEA)/CO₂₃ mL/min)

LCMS: Rt: 0.997 min (LCMS Method 6) MS m/z 487.5 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 6.92-6.90 (m, 1H), 6.89-6.83 (m, 1H),6.73-6.69 (m, 1H), 4.76 (s, 2H), 4.68 (s, 2H), 4.53 (t, J=6.6 Hz, 1H),4.46-4.26 (m, 2H), 4.04-3.85 (m, 2H), 3.18 (d, J=11.0 Hz, 2H), 3.02-2.90(m, 1H), 2.86-2.71 (m, 3H), 2.35-2.13 (m, 5H), 2.08-1.88 (m, 3H),1.83-1.80 (m, 6H), 1.28-1.23 (m, 4H).

Example 11C:(R)-(6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanoneor(S)-(6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanoneand Example 11D:(R)-(6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanoneor

-   (S)-(6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone

To a solution of(1-fluorocyclopropyl)(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone(Intermediate 17H, 200 mg, 0.54 mmol) in DMF (2 mL) was added2-oxaspiro[3.3]heptan-6-yl 4-methylbenzenesulfonate (Intermediate 7A,216 mg, 0.81 mmol) and Cs₂CO₃ (525 mg, 1.61 mmol) at 25° C. The reactionwas stirred at 100° C. for 16 hr. The reaction mixture was filtered andfilter cake was washed with DMF (0.5 mL). The crude product was purifiedby preparative HPLC (XBridge 25×150 mm 5-95% MeCN/H₂O (0.05% mM NH₄HCO₃)and the enantiomers were separated by chiral SFC (Chiralpak® AD 30×250mm column, 70 g/min flow rate, 40% MeOH (0.1% NH₄OH)/CO₂) to give thefaster running enantiomer as Example 11C (36.44 mg, 0.078 mmol) as ayellow gum. The slower running enantiomer was further purified byprep-TLC (DCM:MeOH, 10:1) to give Example 11D (20.03 mg, 0.043 mmol) asa brown gum.

Example 11C

SFC: Rt: 1.740 min (Chiralpak® AD-3 4.6×50 mm, 5-40% EtOH (0.05%DEA)/CO₂ ₃ mL/min).

LCMS: Rt: 1.083 min (LCMS Method 6) MS m/z 469.4 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.17-7.11 (m, 2H), 7.09-7.08 (m, 1H),6.90-6.71 (m, 1H), 4.76 (s, 2H), 4.68 (s, 2H), 4.57 (t, J=6.6 Hz, 1H),4.46-4.26 (m, 2H), 4.07-3.84 (m, 2H), 3.21-3.13 (m, 2H), 3.01-2.91 (m,1H), 2.88-2.68 (m, 3H), 2.35-2.12 (m, 5H), 2.06-1.88 (m, 3H), 1.82-1.79(m, 5H), 1.79-1.76 (m, 1H), 1.28-1.23 (m, 4H).

Example 11D

SFC: Rt: 1.982 min (Chiralpak® AD-3 4.6×50 mm, 5-40% EtOH (0.05%DEA)/CO₂ ₃ mL/min).

LCMS: Rt: 1.075 min (LCMS Method 6) MS m/z 469.4 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.19-7.07 (m, 2H), 6.92-6.85 (m, 1H), 6.72 (d,J=7.7 Hz, 1H), 4.76 (s, 2H), 4.68 (s, 2H), 4.57 (q, J=6.6 Hz, 1H),4.45-4.26 (m, 2H), 4.02-3.84 (m, 2H), 3.16 (d, J=10.4 Hz, 2H), 3.01-2.90(m, 1H), 2.87-2.78 (m, 2H), 2.72 (d, J=4.0 Hz, 1H), 2.36-2.09 (m, 5H),2.05-1.89 (m, 3H), 1.85-1.68 (m, 5H), 1.66-1.53 (m, 1H), 1.32-1.18 (m,4H).

Example 12A:(R)-oxetan-3-yl(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone

3-(2-(trifluoromethoxy)phenyl)pentane-1,5-diylbis(4-methylbenzenesulfonate) (Intermediate 1H, 300 mg, 0.524 mmol) and(R)-(6-amino-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone(Intermediate 2E, 121 mg, 0.576 mmol) were suspended in MeCN (5 mL) atRT and potassium phosphate tribasic (389 mg, 1.834 mmol) was added tothe solution. The reaction was warmed to 90° C. and stirred for 48 h.The solvent was removed under reduced pressure and the solid residue wassuspended in EtOAc. The organic layer was separated and washed withwater and brine, dried over sodium sulfate and concentrated. The residuewas then purified by FCC (0-8% MeOH (1% NH₄OH)/DCM to yield the titlecompound (135 mg, 0.305 mmol).

LCMS: Rt: 2.42 min (LCMS Method 4) MS m/z 439.1 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.41 (d, J=6.8 Hz, 1H), 7.36-7.22 (m, 3H),4.77 (dd, J=8.1, 1.7 Hz, 4H), 4.08-3.76 (m, 5H), 3.23-3.10 (m, 2H),3.03-2.89 (m, 1H), 2.73 (s, 1H), 2.21 (dd, J=12.8, 7.3 Hz, 3H), 1.94(dtd, J=24.0, 13.9, 7.8 Hz, 3H), 1.79 (dt, J=9.3, 4.6 Hz, 5H), 1.68-1.50(m, 1H).

8.2. Biological Activity and Selectivity of Novel Chemical Matter on M1,M2, M3, M4, and M5 Stable Cell Lines

The above examples were characterized by measuring the intracellularmobilization of Ca++ ions caused by signaling events mediated by thereceptor. The Intra-cellular Calcium flux levels were captured by thehighly sensitive Ca++ indicator, Calcium Assay Kit (BD Biosciences,Catalog Number 640178). The fluorescent activity from all receptors weremonitored by the fluorescent imager, FDSS 7000EX (Hamamatsu) over a spanof 3 minutes. The change in Calcium flux was readily captured uponactivation with the muscarinic orthosteric agonist, carbachol.

CHRM4 Cell Line Maintenance

CHO-K₁ cells stably expressing the human cloned CHRM4 receptor (M4_CHOcells) were grown and maintained in a monolayer culture with F12/HAM(Life Technologies) supplemented with 10% Fetal Bovine Serum, 1XPen-Strep, and 0.4 mg/mL Geneticin in a humidified atmosphere (5% CO₂)at 37° C. The cultures were grown to 80-90% confluency in T150 flasks(Corning) and washed with 1X DPBS then lifted with 0.05% Trypsin (LifeTechnologies). The cells were harvested in growth media then spun (1Krpm, 3 minutes) and cryopreserved using Recovery Cell Culture FreezingMedia (Gibco Technologies). Cells were stored in liquid nitrogen andthawed a day before the assay.

CHRM1 Cell Line Maintenance

Cloned human M1 receptor (CHRM1) was stably expressed in HEK293 cellsand were grown and maintained in a monolayer culture with DMEM/HighGlucose (Life Technologies) supplemented with 10% Fetal Bovine Serum, 1XPen-Strep, and 0.5 mg/mL Geneticin in a humidified atmosphere (5% CO₂)at 37° C. The cultures were grown to 90% confluency in T150 flasks(Corning) and washed with 1X DPBS and lifted with 0.05% Trypsin (LifeTechnologies). The cells were then spun (1K rpm, 3 minutes) and frozenusing Recovery Cell Culture Freezing Media (Gibco Technologies). Cellswere stored in liquid nitrogen and thawed a day before the assay.

CHRM2 Cell Line Maintenance

CHO-K1 cells stably expressing the human cloned CHRM2 receptor (M2_CHOcells) were grown and maintained in a monolayer culture with F12/HAM(Life Technologies) supplemented with 10% Fetal Bovine Serum, 1XPen-Strep, and 0.4 mg/mL Geneticin in a humidified atmosphere (5% CO₂)at 37° C. The cultures were grown to 80-9 0% confluency in T150 flasks(Corning) and washed with 1X DPBS and lifted with 0.05% Trypsin (LifeTechnologies). The cells were then spun (1K rpm, 3 minutes) and frozenusing Recovery Cell Culture Freezing Media (Gibco Technologies). Cellswere stored in liquid nitrogen and thawed a day before the assay.

CHRM3 and CHRM5 Cell Line Maintenance

CHO-K₁ cells stably expressing the human cloned CHRM3 receptor (M3_CHOcells) were grown and maintained in a monolayer culture with F12/HAM(Life Technologies) supplemented with 10% Fetal Bovine Serum, 1XPen-Strep, and 0.4 mg/mL Geneticin in a humidified atmosphere (5% CO₂)at 37° C. The cultures were grown to 80-9 0% confluency in T150 flasks(Corning) and washed with 1X DPBS and lifted with 0.05% Trypsin (LifeTechnologies). The cells were then spun (1K rpm, 3 minutes) and frozenusing Recovery Cell Culture Freezing Media (Gibco Technologies). Cellswere stored in liquid nitrogen and thawed a day before the assay. Asimilar procedure was used for cells stably expressing the human clonedCHRM5 receptor (M5_CHO).

CHRM4 Ca++ Flux Assay

Prior to the day of the assay, stable M4_CHO cells were thawed andplated on 384 well black walled clear bottom TC treated plates (GreinerCat #781091) at 12K cells/well using F12/HAM Media supplemented with 10%FBS (Life Technologies) and kept overnight in a humidified atmosphere(5% CO₂) at 37° C. The next day, cells were loaded with 20 L Ca++ dye(BD Biosciences) using Loading Buffer (HBSS+Ca/+Mg, 20 mM HEPES, 2.5 mMProbenecid) and placed back in cell incubator for a minimum of 1 hour.After incubation, the dye was replaced with 45 μL Assay Buffer(HBSS—Ca/—Mg, 20 mM HEPES, 2.5 mM Probenecid) supplemented with 20 μMATP (Sigma Aldrich) and kept at room temperature in the dark for 60minutes before running on a cell imager. The FDSS 7000EX (Hamamatsu) wasused to capture Ca++ traces for a span of 3 minutes from cells treatedwith 11 point dose of compound in triplicate in order to generate doseresponse curves in agonist mode. All compounds were serially diluted inDMSO then prepared in Assay Buffer for Ca++ flux studies. The doseresponse curves were generated from the average of triplicate wellsobtained from each data point and used a non-linear regression of fourparameter dose response algorithm. The Percent Activity (PA) wasmeasured to EC₁₀₀ of Carbachol.

CHRM1 Ca⁺⁺ Flux Assay

Prior to the day of the assay, stable HEK293 M1 cells were thawed andplated on 384 well black walled clear bottom TC treated plates (GreinerCat #781091) at 25K cells/well with DMEM/High Glucose supplemented with10% FBS (Hyclone) Pen-Strep (Life Technologies) and kept overnight in ahumidified atmosphere (5% CO₂) at 37° C. The following day, cells wereloaded with 20 uL Ca++ dye (BD Biosciences) using Loading Buffer(HBSS+Ca/+Mg, 20 mM HEPES) and placed back in cell incubator for aminimum of 1 hour. The dye was replaced with 45 μL Assay Buffer(HBSS—Ca/—Mg, 20 mM HEPES) and kept at room temperature prior to runningon cell imager. Compounds were prepared in Assay Buffer and 5 uL wasadded to the cells. The FDSS 7000EX (Hamamatsu) was used to acquire Ca++traces for 3 minutes from cells treated with 11 point dose in triplicatein order to generate dose response curves in agonist mode. All compoundswere serially diluted in DMSO then prepared in Assay Buffer for Ca⁺⁺flux studies. The dose response curves were generated from the averageof triplicate wells obtained from each data point and used a non-linearregression of four parameter dose response algorithm. The PercentActivity (PA) was measured to EC₁₀₀ of Carbachol.

CHRM2 Ca⁺⁺ Flux Assay

Prior to the day of the assay, stable M2 CHO cells were thawed andplated on Greiner 384 well TC treated plate at a density of 12Kcells/well and kept overnight in a humidified atmosphere (5% CO₂) at 37°C. The following day, the cells were loaded with Ca⁺⁺ dye (BDBiosciences) using Loading Buffer (HBSS+Ca/+Mg, 20 mM HEPES, 2.5 mMProbenecid) and placed back in cell incubator for a minimum of 1 hourand maximum of 2 hours. After incubation, the dye was replaced withAssay Buffer (HBSS—Ca/—Mg, 20 mM HEPES, 2.5 mM Probenecid) supplementedwith 20 μM ATP (Sigma Aldrich) and kept at room temperature for 60minutes prior before running on cell imager. The FDSS 7000EX (Hamamatsu)was used to acquire Ca⁺⁺ traces from cells in response to compoundtreatment and the data was used to generate dose response curves inagonist mode. All compounds were serially diluted in DMSO then preparedin Assay Buffer for Ca⁺⁺ flux studies. The dose response curves weregenerated from the average of triplicate wells obtained from each datapoint and used a non-linear regression of four parameter dose responsealgorithm. The Percent Activity (PA) was measured to EC₁₀₀ of Carbachol.

CHRM3 and CHRM5 Ca⁺⁺ Flux Assay

Prior to the day of the assay, stable M3_CHO or M5_CHO cells were thawedand plated on Greiner 384 well black TC treated plates at 12K cells/wellin F12/DMEM supplemented with 10% FBS (Hyclone) and kept overnight in ahumidified atmosphere (5% CO₂) at 37° C. The next day, cells were loadedwith Ca⁺⁺ dye (BD Biosciences) using Loading Buffer (HBSS+Ca/+Mg, 20 mMHEPES, 2.5 mM Probenecid) and placed back in cell incubator for aminimum of 1 hour. After incubation, the dye was replaced with AssayBuffer (HBSS—Ca/—Mg, 20 mM HEPES, 2.5 mM Probenecid) and kept at roomtemperature in the dark before running on cell imager. The FDSS 7000EX(Hamamatsu) was used to acquire Ca⁺⁺ traces from cells treated with 11point dose response of compounds in triplicate in order to generate doseresponse curves in agonist mode. All compounds were serially diluted inDMSO then prepared in Assay Buffer for Ca⁺⁺ flux studies. The doseresponse curves were generated from the average of triplicate wellsobtained from each data point and used a non-linear regression of fourparameter dose response algorithm. The Percent Activity (PA) wasmeasured to EC₁₀₀ of Carbachol.

If an Example was tested more than once in an assay, then the valuesbelow represent the geometric mean of the results from each independentexperiment.

TABLE 20 Ca⁺⁺ Flux Assay Results M1 M1 M2 M2 M3 M3 M4 M4 M5 M5 FDSS FDSSFDSS FDSS FDSS FDSS FDSS FDSS FDSS FDSS EC50 PA EC50 PA EC50 PA EC50 PAEC50 PA Example (μM) % (μm) % (μM) % (μM) % (μM) % Example 0.237 63 <250 <25 0 0.001 81 <25 0 1A Example 0.322 48 <25 0 <25 0 0.001 69 <25 0 1BExample 0.056 85 0.017 15 <25 0 <0.0004 75 <25 0 1C Example 0.019 890.035 40 <25 0 0.001 79 4.387 0 1D Example 0.057 85 0.021 14 <25 0 0.00172 <25 0 1E Example 0.031 79 <25 0 <25 0 0.004 48 <25 0 1F Example 0.07280 0.075 38 <25 0 0.001 82 <25 0 1G Example 0.048 88 0.030 41 <25 00.001 71 2.015 10 1H Example 0.616 55 0.092 28 <25 0 0.004 61 <25 0 1IExample 0.182 78 0.051 72 <25 0 0.006 50 <25 0 1J Example 0.024 85 0.02919 <25 0 0.001 74 <25 0 1K Example 0.166 42 0.214 28 <25 0 0.002 67 <250 1L Example 1.548 11 0.402 30 <25 0 0.003 53 <25 0 1M Example 0.069 700.007 10 <25 0 <0.0004 62 <25 0 1N Example <25 0 <25 0 <25 0 0.003 59<25 0 1O Example 0.098 43 0.007 7 <25 0 0.001 61 <25 0 1P Example 0.14774 0.117 12 <25 0 0.010 69 <25 0 2A Example 0.036 107 0.039 32 <25 0<0.0004 95 <25 0 2B Example 0.059 79 <25 0 <25 0 0.001 72 <25 0 2CExample 0.141 82 0.050 8 <25 0 0.001 72 <25 0 2D Example 0.381 78 0.09010 <25 0 0.002 86 <25 0 2E Example 0.277 112 0.064 22 <25 0 0.007 88 <250 2F Example 0.429 51 0.136 19 <25 0 0.007 70 <25 0 2G Example 0.178 610.458 32 <25 0 0.003 83 <25 0 2H Example 0.106 89 0.125 41 <25 0 0.00196 <25 0 2I Example 0.046 97 0.036 37 <25 0 0.002 92 <25 0 2J Example0.133 97 0.159 29 <25 0 0.003 93 <25 0 2K Example 0.540 69 <25 0 <25 00.011 77 <25 0 2L Example 0.093 99 0.343 18 <25 0 0.006 82 <25 0 2MExample 0.302 69 <25 0 <25 0 0.001 81 <25 0 2N formate sale Example0.081 77 0.090 28 <25 0 <0.0004 89 <25 0 2O formate salt Example 0.00892 0.076 21 <25 0 <0.0004 88 <25 0 3A Example 0.051 83 0.018 16 <25 00.001 70 <25 0 3B Example 0.041 88 0.024 18 <25 0 0.002 66 <25 0 3CExample 0.042 78 <25 17 <25 0 0.002 71 <25 0 3D Example 0.054 87 0.19131 <25 0 0.003 87 <25 0 3E Example 0.040 68 <25 0 <25 0 0.006 60 <25 03F Example 0.135 66 0.304 20 <25 0 0.007 57 <25 0 3G Example 0.020 84<25 0 <25 0 0.008 48 <25 0 3H Example 0.054 70 <25 40 <25 0 0.001 70 <250 3I Example 0.085 58 <25 0 <25 0 0.004 57 <25 0 3J Example 0.186 57 <250 <25 0 0.005 68 <25 0 3K Example 0.062 67 <25 0 <25 0 0.019 34 <25 0 3LExample <25 0 <25 0 <25 0 0.018 30 <25 0 3M Example <25 0 <25 0 <25 0<25 0 <25 0 3N Example <25 0 <25 0 <25 0 <25 1 <25 0 3O Example 0.015 830.019 21 <25 0 <0.0004 77 0.700 6 4A Example 0.105 64 <25 0 <25 0 0.00264 <25 0 5A formate salt Example 0.191 35 <25 0 <25 0 0.004 53 <25 0 5Bformate salt Example 0.420 69 <25 0 <25 0 <25 6 <25 0 5C formate saltExample <25 0 <25 0 <25 0 0.156 36 <25 0 5D Example <25 0 <25 0 <25 0<25 2 <25 0 5E Example 3.762 7 <25 26 <25 0 0.006 59 14.316 17 5FExample <25 0 <25 0 <25 0 <25 1 <25 0 5G Example 0.048 50 <25 0 <25 00.001 61 <25 0 5H Example 0.272 55 13.189 49 <25 0 0.084 16 <25 0 5IExample 0.100 60 <25 0 <25 0 0.009 60 <25 0 5J Example 0.284 54 <25 18<25 0 0.009 64 <25 0 5K Example <25 0 7.879 36 11.72 0 0.029 61 14.41717 5L Example <25 0 <25 0 <25 0 0.051 43 <25 0 5M Example <25 0 <25 3511.27 9 0.026 50 22.941 8 5N Example 1.335 27 <25 0 <25 0 0.055 39 <25 05O Example 0.196 60 <25 16 <25 0 0.043 55 13.425 8 5P Example <25 0 <250 <25 0 0.021 54 <25 0 5Q Example 2.033 41 <25 0 <25 0 0.131 51 <25 1 5RExample 1.044 45 <25 0 <25 0 0.129 55 <25 0 5S Example 0.537 34 <25 0<25 0 0.063 25 <25 0 5T Example 0.672 2 <25 0 <25 0 0.028 49 <25 0 5UExample 0.215 60 <25 0 <25 0 0.020 59 <25 0 5V Example 0.052 60 0.057 16<25 0 0.001 90 <25 0 5W Example <25 0 <25 0 <25 0 0.054 24 <25 0 5XExample <25 0 <26 0 <25 0 <25 0 <25 0 5Y Example 0.413 21 <25 0 <25 00.042 44 <25 0 5Z Example 0.102 61 1.769 28 <25 0 0.010 83 <25 0 5AAExample 0.201 72 0.739 13 <25 0 0.017 80 <25 0 5BB Example 0.335 360.466 35 <25 0 0.022 84 <25 0 5CC Example 1.264 0 >25 0 >25 0 0.08226 >25 0 5DD Example 0.003 73 0.032 10 <25 0 0.001 52 <25 0 6A Example0.012 90 <25 0 <25 0 0.005 50 <25 0 6B Example 0.030 83 <25 0 <25 00.008 50 <25 0 6C Example 0.018 18 <25 0 <25 0 0.011 53 <25 0 6D Example0.12 67 <25 0 <25 0 0.003 65 <25 0 6E Example 0.009 75 0.142 55 9.78 90.004 71 <25 0 7A Example 0.015 78 0.651 77 <25 0 0.004 44 <25 0 7BExample 0.011 87 <25 0 <25 0 0.004 39 <25 0 7C Example 0.003 114 0.09231 <25 0 0.002 57 2.196 16 7D Example 0.046 101 0.141 23 <25 0 0.003 591.563 13 7E Example 0.042 75 <25 0 <25 0 0.014 60 <25 0 7F Example 0.03765 <25 0 <25 0 0.009 61 <25 0 7G Example 0.009 71 <25 0 <25 0 0.004 70<25 0 7H Example 0.015 86 0.123 16 <25 0 0.007 55 <25 0 7I Example 0.02481 0.207 33 <25 0 0.006 65 <25 0 7J Example 0.024 72 0.590 23 <25 00.009 76 <25 0 7K Example 0.324 85 <25 0 <25 0 0.020 58 <25 0 7L Example0.010 84 <25 0 <25 0 0.001 50 <25 0 7M Example 0.022 45 <25 0 <25 00.001 68 <25 0 7N Example 0.037 57 <25 0 <25 0 0.009 42 <25 0 7O Example0.029 46 <25 0 <25 0 0.001 49 <25 0 7P Example 0.135 37 <25 0 <25 00.003 48 <25 0 7Q Example <25 0 6.595 15 <25 0 0.062 36 <25 0 7R Example<25 0 <25 0 <25 0 2.647 26 <25 0 7S Example 4.346 32 18.60 19 <25 012.12 5 <25 0 7T Example <25 0 <25 0 <25 0 <25 1 <25 0 7U Example 2.30418 <25 0 <25 0 0.353 23 <25 0 7V Example 0.002 80 <25 0 <25 0 <0.0004 670.077 8 7W Example 0.003 86 <25 0 <25 0 <0.0004 66 0.071 9 7X Example0.246 67 <25 0 <25 0 0.022 49 <25 0 7Y Example 0.211 77 <25 0 <25 00.009 50 <25 0 7Z Example 0.139 57 <25 0 <25 0 0.011 54 <25 0 7AAExample 0.013 55 <25 0 <25 0 0.002 38 <25 0 7BB Example 0.006 94 <25 0<25 0 0.005 46 2.009 9 7CC Example 0.116 86 <25 0 <25 0 0.027 42 1.12018 7DD Example 0.073 98 0.464 17 <25 0 0.006 61 <25 0 7EE Example 0.1827 <25 0 <25 0 0.005 38 <25 0 7FF Example 0.039 91 0.724 9 <25 0 0.007 480.974 14 7GG Example 0.159 82 0.154 16 <25 0 0.019 50 <25 0 7HH Example0.103 89 6.885 12 <25 0 0.009 50 1.640 13 7II Example 0.012 87 0.098 22<25 0 0.002 49 0.935 9 7JJ Example 0.011 80 0.091 21 <25 0 0.002 47 <250 7KK Example 0.438 16 <25 0 <25 0 0.036 43 <25 0 8A Example 0.030 63<25 0 <25 0 0.001 64 <25 0 8B Example 0.030 90 0.203 22 <25 0 0.006 65<25 0 8C Example 2.024 30 <25 0 <25 0 0.347 43 <25 0 8D Example 0.014 920.096 26 <25 0 0.002 61 2.155 1 8E citrate salt Example <25 0 <25 0 <250 1.106 10 <25 0 8F citrate salt Example <25 0 <25 0 <25 0 0.274 24 <250 8G Example 2.651 43 11.792 31 <25 0 0.342 36 <25 0 9A Example 0.047 55<25 0 <25 0 0.005 66 <25 0 9B Example 0.048 27 <25 0 <25 0 0.001 54 <250 9C Example 1.773 23 <26 0 <25 0 0.075 43 <25 0 9D Example 0.120 34 <250 <25 0 0.001 55 <25 0 9E Example <25 0 <25 0 <25 0 0.156 47 <25 0 9FExample 0.301 16 <25 0 <25 0 0.076 14 <25 0 9G Example <25 0 <25 0 <25 0<25 0 <25 0 9H Example 0.092 23 <25 0 <25 0 0.015 17 <25 0 9I Example2.691 3 <25 0 <25 0 0.241 1 <25 0 9J Example 0.036 58 <25 0 <25 −1 0.00156 <25 0 9K Example 0.569 31 <25 0 <25 0 0.026 49 <25 0 9L Example 6.4400 <25 0 <25 0 0.100 35 <25 0 9M Example 1.331 34 <25 42 <25 0 0.005 60<25 0 10A Example <25 o 14.416 31 <25 0 0.045 41 <25 0 10B Example 0.08076 0.035 30 <25 0 <0.0004 62 <25 0 10C Example 1.409 55 0.506 11 <25 00.025 50 <25 0 10D Example 3.987 4 3.987 11 <25 0 0.027 59 <25 0 10EExample <25 0 <25 0 <25 0 0.0047 71 <25 0 10F Example 0.063 64 <25 0 <250 0.005 56 <25 0 10G Example 1.390 36 <25 0 <25 0 0.019 51 <25 0 10HExample <25 0 <25 0 <25 0 1.068 17 <25 0 10I Example 0.020 66 <25 42 <250 0.001 67 14.057 0 10J Example 0.094 65 <25 0 <25 0 0.007 65 <25 0 10KExample 0.736 50 13.181 44 12.41 2 0.098 57 <25 2 10L Example 0.04977 >25 0 >25 0 0.011 67 >25 0 10M Example <25 0 <25 28 <25 0 <25 1 <25 010N Example 0.044 83 <25 17 <25 0 0.001 67 <25 0 10O Example 0.700 20<25 0 <25 0 0.093 48 <25 0 10P Example 0.170 66 <25 18 <25 0 0.008 71<25 0 10Q Example <25 0 <25 0 <25 0 0.122 36 <25 0 10R Example 3.92 21<25 0 <25 0 0.170 67 <25 0 10T Example <25 9 <25 0 <25 0 0.038 45 <25 011A Example 0.030 9 <25 0 <25 0 0.002 51 <25 0 11B Example <25 1 <25 0<25 −1 0.002 47 <25 0 11C Example <25 1 <25 0 <25 0 0.097 38 <25 0 11DExample 0.008 79 110 18 <25 0 0.002 73 <25 0 12A

Testing Novel Compounds in a Mouse Amphetamine Induced HyperlocomotionAssay

The aim of these studies is to determine the effect of test compounds onthe hyperactivity in mice induced by the stimulant d-amphetamine.Clinically efficacious muscarinic antipsychotics such as xanomeline areactive in this assay and it is therefore considered appropriate as atest for novel M4 agonists. Studies described in this report wereperformed in a manner approved by the Novartis Institutes for BioMedicalResearch, Inc. Animal Care and Use Committee. Treatment groups wererandomized and counterbalanced by chamber and run. Locomotor activitywas assessed in an open-field (40 cm×40 cm) setup. Each chamber isenclosed behind light-blocking curtains and illuminated by an LED light.Mice were acclimated to the room for a minimum of 60 minutes and thenadministered test article (Vehicle, dose 1, dose 2, dose 3, PO) justprior to being placed in the chamber for the habituation (minutes 1-30)phase. After the habituation phase mice were administered eitherd-amphetamine (2.0 mg/kg) or Saline (IP), as well as Xanomeline as apositive control (1.0 mg/kg, SC) if they did not previously receive a POinjection of test article. The injection volume for all injections was10 mL/kg. Measurements were captured via infrared beam breaks byAccuscan hardware and Superflex 5.6 software. Locomotor activity wasmonitored for an additional 2-hour test phase (minutes 31-150) afteramphetamine injections. Animals were returned to their home cage andhousing location after the conclusion of the test.

Data Analysis

All statistical analyses were performed within Graphpad Prism 7.04.AUC's were calculated by summing the distance traveled during each the10-minute bins and compared via t-test or one-way ANOVA. A t-testcomparing the AUC30-150 of the d-Amphetamine-vehicle injected group tothe vehicle-vehicle injected group determined whether d-amphetamineproduced an effective stimulation of activity. An ordinary one-way ANOVAwas performed to compare each test compound-treated group to thed-Amphetamine-vehicle group using a Dunnett's multiple comparison test.Because d-Amphetamine is primarily active during the first hour of thetest phase, these analyses are performed on the first half (minutes31-90). A p-value of <0.05 was considered statistically significant.Data for Examples 2H, 6E, 8C, and 9B are shown in FIG. 1 and the datafor Example 12A is shown in FIG. 2 .

Altogether, the experimental data presented herein indicate that thedisclosed compounds are potent and highly selective M4 receptor agonists(see Table 20) and are effective in vivo as indicated by their efficacyin reducing hyperactivity induced by the stimulant d-amphetamine in micein a dose-dependent manner (see FIG. 1-2 ).

1. A method for the treatment of psychosis comprising administration of a therapeutically effective amount of a compound according to Formula (I) or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the compound according to Formula (I) is

R¹ is halogen or hydrogen; R² is halogen or hydrogen; R³ is C₁₋₆ alkyl, said alkyl is optionally substituted with one or two substituents independently selected from the group consisting of 4 to 6-membered heterocycloalkyl and —OH, 5 to 6-membered heteroaryl, 3 to 6-membered cycloalkyl, said cycloalkyl is optionally substituted with one —OH, 5 to 6-membered heterocycloalkyl, said heterocycloalkyl is optionally substituted with one —OH, or —OR⁴; R⁴ is —CF₃, —CF₂H, C₁₋₆ alkyl, said alkyl is optionally substituted with one or two R⁶, 3 to 6-membered cycloalkyl, 4 to 7-membered heterocycloalkyl, said heterocycloalkyl is optionally substituted with one R⁶, 5 to 6-membered heteroaryl, or R⁴ is one of the following groups:

R⁵ is halogen or hydrogen; each R⁶ is independently halogen, —OH, —CF₃, —CF₂H, cyano, —OCF₃, —OCH₃, —O-heterocycloalkyl, C₁-C₄ alkyl, 4 to 7-membered heterocycloalkyl, said heterocycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of halogen, —OH, and C₁₋₃ alkyl, 5 to 6-membered heteroaryl, said heteroaryl is optionally substituted with one or two C₁₋₃ alkyl, 3 to 6-membered cycloalkyl, said cycloalkyl is optionally substituted with one —CF³, or each of R⁶ is independently one of the following groups:

R⁷ is a 5 to 6-membered heteroaryl, said heteroaryl is optionally substituted with one substituent selected from the group consisting of C₁-C₆ alkyl, —CF₃, and halogen, or C(O)R⁸; and R⁸ is 3 to 6-membered cycloalkyl, said cycloalkyl is optionally substituted with one halogen, or 4 to 6-membered heterocycloalkyl.
 2. The compound according to claim 1 of Formula (Ia)

or a pharmaceutically acceptable salt or stereoisomer thereof.
 3. The compound according to claim 1 of Formula (Ib)

or a pharmaceutically acceptable salt or stereoisomer thereof.
 4. The method according to claim 1, wherein R¹ is selected from the group consisting of H, chloro, and fluoro.
 5. The method according to claim 1, wherein R² is H or fluoro.
 6. The method according to claim 1, wherein R⁵ is H or fluoro.
 7. The method according to claim 1, wherein R¹, R², and R⁵ are H.
 8. The method according to claim 1, wherein R³ is selected from the group consisting of:


9. The method according to claim 1, wherein R³ is —OR⁴.
 10. The method according to claim 1, wherein R⁴ is selected from the group consisting of —CH₃, —CF₃, —CF₂H, —CH₂CH₃, —CH(CH₃)₂, —CH₂CF₂H, —CH₂CH₂F, —(CH₂)₂CF₃, —CH₂C(CH₃)₂F, —(CH₂)₂OCF₃, —(CH₂)₂OH, —(CH₂)₂OCH₃, —CH₂C(CH₃)₂OH, —(CH₂)₂C(CH₃)₂OH, —(CH₂)₂C(CH₃)₂OCH₃, —CH₂C(CH₃)₂OCH₃, —(CH₂)₂CN, and —CH₂CH(CH₃)₂.
 11. The method according to claim 1, wherein R⁴ is selected from the group consisting of:


12. The method according to claim 1, wherein R⁷ is 5 to 6-membered heteroaryl or —C(O)R⁸.
 13. The method according to claim 1, wherein R⁷ is


14. The method according to claim 1, wherein R⁷ is —C(O)R⁸.
 15. The method according to claim 14, wherein R⁸ is 4 to 6-membered heterocycloalkyl or 3 to 6-membered cycloalkyl.
 16. The method according to claim 14, wherein R⁸ is 4 to 6-membered heterocycloalkyl.
 17. The method according to claim 14, wherein R⁸ is


18. The method according to claim 14, wherein R⁸ is 3 to 6-membered cycloalkyl, said 3 to 6-membered cycloalkyl is substituted with one halogen.
 19. A method for the treatment of psychosis comprising administration of a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the compound is selected from the group consisting of: (R)-2-(6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole; (R)-2-(6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole; 2-((R)-6-(4-(2-(((R)-1,4-dioxan-2-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole; (R)-2-(6-(4-(2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole; 2-((R)-6-(4-(2-(((S)-1,4-dioxan-2-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole; (R)-ethyl 5-(6-(4-(2-hydroxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole-2-carboxylate; (R)-2-(6-(4-(2-(oxetan-3-ylmethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole; (R)-2-(6-(4-(2-((3-fluorooxetan-3-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole; (R)-2-(6-(4-(2-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole; (R)-2-(6-(4-(2-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole; (R)-6-(4-(2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane; (R)-2-(pyrimidin-5-yl)-6-(4-(2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane; (R)-2-(pyrimidin-5-yl)-6-(4-(2-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane; (R)-6-(4-(2-(oxetan-3-ylmethoxy)phenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane; (R)-6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)phenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane; (R)-2-(pyrimidin-5-yl)-6-(4-(2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane; (R)-1-(2-(1-(2-(1,3,4-oxadiazol-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)-2-methylpropan-2-ol; 2-((R)-6-(4-(2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole; (R)-ethyl 5-(6-(4-(2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole-2-carboxylate; (R)-2-(6-(4-(2-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole; (R)-2-(6-(4-(2-((4-methyltetrahydro-2H-pyran-4-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole; (R)-2-(6-(4-(2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole; (R)-2-(6-(4-(2-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole; (R)-2-(6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole; (R)-2-(6-(4-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole; 2-((6R)-6-(4-(5-fluoro-2-(tetrahydrofuran-3-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole; 2-((6R)-6-(4-(2-(tetrahydrofuran-3-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole; (R)-2-(6-(4-(2-((tetrahydro-2H-pyran-4-yl)methyl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole; (R)-2-(6-(4-(2-(oxazol-2-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole; (1S,4s)-4-(2-(1-((R)-2-(1,3,4-oxadiazol-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenyl)cyclohexan-1-ol; (1R,4r)-4-(2-(1-((R)-2-(1,3,4-oxadiazol-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenyl)cyclohexan-1-ol; (1s,4r)-4-(2-(1-((R)-2-(1,3,4-oxadiazol-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenyl)cyclohexan-1-ol; (1r,4r)-4-(2-(1-((R)-2-(1,3,4-oxadiazol-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenyl)cyclohexan-1-ol; (R)-2-(6-(4-(2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole; 2-((R)-6-(4-(2-(((R)-1,4-dioxan-2-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole; 2-((R)-6-(4-(2-(((S)-1,4-dioxan-2-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole; (R)-2-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole; (R)-2-(6-(4-(3-fluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole; (R)-2-(6-(4-(2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole; (R)-1-(2-(1-(2-(1,3,4-thiadiazol-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)-2-methylpropan-2-ol; (R)-4-(2-(1-(2-(1,3,4-thiadiazol-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)-2-methylbutan-2-ol; (R)-5-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)isothiazole; (R)-5-(6-(4-(2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,2,4-thiadiazole; (R)-1-(2-(1-(2-(1,2,4-thiadiazol-5-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)-2-methylpropan-2-ol; (R)-4-(2-(1-(2-(1,2,4-thiadiazol-5-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)-2-methylbutan-2-ol; (R)-5-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-3-methyl-1,2,4-thiadiazole; (R)-1-(5-fluoro-2-(1-(2-(4-methyloxazol-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)-2-methylpropan-2-ol; (R)-2-methyl-1-(2-(1-(2-(4-methyloxazol-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)propan-2-ol; (R)-3-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,2,4-oxadiazole; (R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane formate salt; (R)-2-methyl-1-(2-(1-(2-(pyrimidin-5-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)propan-2-ol formate salt; (R)-2-methyl-1-(2-(1-(2-(4-methylpyrimidin-5-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)propan-2-ol formate salt; (R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(6-methylpyridin-3-yl)-2-azaspiro[3.4]octane formate salt; (R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(2-methylpyrimidin-5-yl)-2-azaspiro[3.4]octane; (R)-2-(5-fluoropyridin-3-yl)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octane; (R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(6-methylpyrazin-2-yl)-2-azaspiro[3.4]octane; (R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(pyrazin-2-yl)-2-azaspiro[3.4]octane; (R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(3-(trifluoromethyl)pyrazin-2-yl)-2-azaspiro[3.4]octane; (R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(3-methylpyrazin-2-yl)-2-azaspiro[3.4]octane; (R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(pyridin-3-yl)-2-azaspiro[3.4]octane; (R)-2-(6-methylpyridin-3-yl)-6-(4-(2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane; (R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(4-methyl-1,3,5-triazin-2-yl)-2-azaspiro[3.4]octane; (R)-2-(6-chloropyridazin-3-yl)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octane; (R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(pyridazin-3-yl)-2-azaspiro[3.4]octane; (R)-6-(4-(5-chloro-2-methoxyphenyl)piperidin-1-yl)-2-(pyridazin-4-yl)-2-azaspiro[3.4]octane; (R)-6-(4-(2-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)piperidin-1-yl)-2-(1,3,5-triazin-2-yl)-2-azaspiro[3.4]octane; (R)-2-(3,6-dichloropyridazin-4-yl)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octane; (R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(pyridazin-4-yl)-2-azaspiro[3.4]octane; (R)-2-methyl-1-(2-(1-(2-(3-methylpyrazin-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)propan-2-ol; (R)-1-(2-(1-(2-(1,3,5-triazin-2-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)-2-methylpropan-2-ol; (R)-6-(4-(5-fluoro-2-methoxyphenyl)piperidin-1-yl)-2-(pyridazin-4-yl)-2-azaspiro[3.4]octane; (R)-6-(4-(3-fluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane; (R)-6-(4-(2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-2-(pyridazin-3-yl)-2-azaspiro[3.4]octane; (R)-6-(4-(2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-2-(5-methylpyrazin-2-yl)-2-azaspiro[3.4]octane; (R)-6-(4-(2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-2-(pyridazin-4-yl)-2-azaspiro[3.4]octane; (R)-2-(5-fluoropyridin-3-yl)-6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane; (R)-2-(pyrimidin-5-yl)-6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane; (R)-2-(6-fluoropyridin-3-yl)-6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane; (R)-6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-(5-methylpyrazin-2-yl)-2-azaspiro[3.4]octane; (R)-(6-(4-(5-fluoro-2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone; (R)-(6-(4-(2-(difluoromethoxy)-4-fluorophenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone; (R)-(6-(4-(4-fluoro-2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone; (R)-(6-(4-(4-fluoro-2-isopropoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone; (R)-(6-(4-(2-cyclopropoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone; (R)-(6-(4-(2-(2-fluoro-2-methylpropoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone; (R)-oxetan-3-yl(6-(4-(2-(thiazol-2-yloxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone; (R)-3-(2-(1-(2-(oxetane-3-carbonyl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)propanenitrile; oxetan-3-yl((R)-6-(4-(2-(((R)-tetrahydrofuran-3-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone; (R)-(6-(4-(2-isobutoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone; (R)-(6-(4-(2-(cyclopentyloxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone; (R)-(6-(4-(2-cyclobutoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone; (R)-(6-(4-(2-(cyclopropylmethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone; (R)-(6-(4-(2-ethoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone; (R)-(6-(4-(2-isopropoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone; (R)-(6-(4-(2-(2-hydroxy-2-methylpropoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone; (R)-(1-fluorocyclopropyl)(6-(4-(2-(pyrimidin-2-ylmethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone; (S)-(1-fluorocyclopropyl)(6-(4-(2-(pyrimidin-2-ylmethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone; (R)-(1-fluorocyclopropyl)(6-(4-(2-(2-hydroxyethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone; (S)-(1-fluorocyclopropyl)(6-(4-(2-(2-hydroxyethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone; (R)-(6-(4-(2-(cyclopropylmethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone; (R)-(6-(4-(2-(cyclopropylmethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone; (R)-1-(2-(2-(1-(2-(1-fluorocyclopropane-1-carbonyl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)ethyl)pyrrolidin-2-one formate salt; (S)-1-(2-(2-(1-(2-(1-fluorocyclopropane-1-carbonyl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenoxy)ethyl)pyrrolidin-2-one formate salt; (R)-(1-fluorocyclopropyl)(6-(4-(2-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone; (S)-(1-fluorocyclopropyl)(6-(4-(2-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone; (R)-(1-fluorocyclopropyl)(6-(4-(2-((5-methyl-1,3,4-thiadiazol-2-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone; (S)-(1-fluorocyclopropyl)(6-(4-(2-((5-methyl-1,3,4-thiadiazol-2-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone; (R)-(6-(4-(2-ethoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone; (S)-(6-(4-(2-ethoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone; (R)-(6-(4-(2-(cyclopropylmethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone; (R)-(6-(4-(2-(cyclopropylmethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone; (R)-(6-(4-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone; (S)-(6-(4-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone; (R)-(1-fluorocyclopropyl)(6-(4-(2-((2-methyloxazol-5-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone; (S)-(1-fluorocyclopropyl)(6-(4-(2-((2-methyloxazol-5-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone; (R)-(1-fluorocyclopropyl)(6-(4-(2-((5-methyl-1,3,4-oxadiazol-2-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone; (S)-(1-fluorocyclopropyl)(6-(4-(2-((5-methyl-1,3,4-oxadiazol-2-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone; (R)-(1-fluorocyclopropyl)(6-(4-(2-((5-methyl-1,2,4-oxadiazol-3-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone; (S)-(1-fluorocyclopropyl)(6-(4-(2-((5-methyl-1,2,4-oxadiazol-3-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone; (R)-(1-fluorocyclopropyl)(6-(4-(2-((5-methyl-1,3,4-oxadiazol-2-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone; (S)-(1-fluorocyclopropyl)(6-(4-(2-((5-methyl-1,3,4-oxadiazol-2-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone; (R)-(1-fluorocyclopropyl)(6-(4-(2-((5-methyl-1,2,4-oxadiazol-3-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone; (S)-(1-fluorocyclopropyl)(6-(4-(2-((5-methyl-1,2,4-oxadiazol-3-yl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone; (R)-(1-fluorocyclopropyl)(6-(4-(2-(3,3,3-trifluoropropoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone; (S)-(1-fluorocyclopropyl)(6-(4-(2-(3,3,3-trifluoropropoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone; (R)-(1-fluorocyclopropyl)(6-(4-(2-(3-hydroxy-3-methylbutoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone; (S)-(1-fluorocyclopropyl)(6-(4-(2-(3-hydroxy-3-methylbutoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone; (R)-(6-(4-(2-(3-hydroxy-3-methylbutoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone; (R)-oxetan-3-yl(6-(4-(2-(2-(trifluoromethoxy)ethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone; (R)-oxetan-3-yl(6-(4-(2-(2-(oxetan-3-yloxy)ethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone; (R)-(1-fluorocyclopropyl)(6-(4-(2-(3-methoxy-3-methylbutoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone; (S)-(1-fluorocyclopropyl)(6-(4-(2-(3-methoxy-3-methylbutoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone; (R)-oxetan-3-yl(6-(4-(2-(3,3,3-trifluoropropoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone; (R)-(6-(4-(2-(2-methoxy-2-methylpropoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone; (R)-oxetan-3-yl(6-(4-(2-((1-(trifluoromethyl)cyclopropyl)methoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone; (R)-(6-(4-(2-(2,2-difluoroethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone; (R)-oxetan-3-yl(6-(4-(2-(2-(oxetan-3-yl)ethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone; (S)-(6-(4-(5-chloro-2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone; (R)-(6-(4-(5-chloro-2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone; (S)-(6-(4-(5-chloro-2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone; (R)-(6-(4-(5-chloro-2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone; (S)-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone; (R)-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone; (S)-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone; (R)-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone; (S)-(6-(4-(2-(difluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone; (R)-(6-(4-(2-(difluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone citrate salt; (S)-(6-(4-(2-(difluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone; (R)-(6-(4-(2-(difluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(oxetan-3-yl)methanone citrate salt; (S)-oxetan-3-yl(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone; (R)-oxetan-3-yl(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone; (R)-(1-fluorocyclopropyl)(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone; (S)-(1-fluorocyclopropyl)(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone; (R)-(1-fluorocyclopropyl)(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone; (S)-(1-fluorocyclopropyl)(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone; (R)-(6-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone; (S)-(6-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone; (R)-(6-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone; (S)-(6-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone; (R)-(1-fluorocyclopropyl)(6-(4-(2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone; (S)-(1-fluorocyclopropyl)(6-(4-(2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone; (R)-(1-fluorocyclopropyl)(6-(4-(2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone; (S)-(1-fluorocyclopropyl)(6-(4-(2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone; (R)-(1-fluorocyclopropyl)(6-(4-(2-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone; (S)-(1-fluorocyclopropyl)(6-(4-(2-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone; (R)-(1-fluorocyclopropyl)(6-(4-(2-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone; (S)-(1-fluorocyclopropyl)(6-(4-(2-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone; (R)-(6-(4-(5-fluoro-2-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone; (S)-(6-(4-(5-fluoro-2-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone; (R)-(6-(4-(5-fluoro-2-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone; (S)-(6-(4-(5-fluoro-2-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone; (R)-(6-(4-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone; (S)-(6-(4-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone; (R)-(6-(4-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone; (S)-(6-(4-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone; (R)-(1-fluorocyclopropyl)(6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone; (S)-(1-fluorocyclopropyl)(6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone; (R)-6-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-(5-fluoropyridin-3-yl)-2-azaspiro[3.4]octane; (S)-6-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-(5-fluoropyridin-3-yl)-2-azaspiro[3.4]octane; (R)-6-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-(5-fluoropyridin-3-yl)-2-azaspiro[3.4]octane; (S)-6-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-(5-fluoropyridin-3-yl)-2-azaspiro[3.4]octane; (R)-6-(4-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane; (S)-6-(4-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane; (R)-6-(4-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane; (S)-6-(4-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane; (R)-6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane; (S)-6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane; (R)-6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane; (S)-6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane; (R)-6-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane; (S)-6-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane; (R)-6-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane; (S)-6-(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidin-1-yl)-2-(pyrimidin-5-yl)-2-azaspiro[3.4]octane; (S)-2-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)oxazole; (R)-2-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)oxazole; (S)-2-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)oxazole; (R)-2-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)oxazole; (R)-2-(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)oxazole; (S)-2-(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)oxazole; (R)-2-(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)oxazole; (S)-2-(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)oxazole; (R)-2-(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole; (S)-2-(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole; (R)-2-(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole; (S)-2-(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole; (R)-2-(6-(4-(2-(difluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole; (S)-2-(6-(4-(2-(difluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole; (R)-2-(6-(4-(2-(difluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole; (S)-2-(6-(4-(2-(difluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-thiadiazole; (R)-5-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,2,4-thiadiazole; (S)-5-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,2,4-thiadiazole; (R)-5-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,2,4-thiadiazole; (S)-5-(6-(4-(2-methoxyphenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,2,4-thiadiazole; (R)-(6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone; (S)-(6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone; (R)-(6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone; (S)-(6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)-5-fluorophenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone; (R)-(6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone; (S)-(6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone; (R)-(6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone; and (S)-(6-(4-(2-((2-oxaspiro[3.3]heptan-6-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)(1-fluorocyclopropyl)methanone, and pharmaceutically acceptable salts thereof.
 20. The method according to claim 19, wherein the compound is selected from the group consisting of: (R)-2-(6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole; (S)-2-(6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole; (R)-(1-fluorocyclopropyl)(6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone; (S)-(1-fluorocyclopropyl)(6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone; (R)-2-(pyrimidin-5-yl)-6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane; (S)-oxetan-3-yl(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone; and (R)-oxetan-3-yl(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone, and pharmaceutically acceptable salts thereof.
 21. The method according to claim 19, wherein the compound is selected from the group consisting of: (R)-2-(6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole, having the following structure:

(R)-(1-fluorocyclopropyl)(6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone, having the following structure:

(R)-2-(pyrimidin-5-yl)-6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane, having the following structure:

and (R)-oxetan-3-yl(6-(4-(2-(trifluoromethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone, having the following structure:

and pharmaceutically acceptable salts thereof.
 22. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof. 23-25. (canceled)
 25. The method according to claim 1, wherein the psychosis is associated with Alzheimer's disease or frontotemporal dementia.
 26. The method according to claim 19, wherein the psychosis is associated with Alzheimer's disease or frontotemporal dementia. 27-31. (canceled)
 32. The method of claim 21, wherein the compound is (R)-2-(6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole, having the following structure:

or a pharmaceutically acceptable salt thereof.
 33. The method of claim 21, wherein the compound is (R)-(1-fluorocyclopropyl)(6-(4-(2-(tetrahydro-2H-pyran-4-yl)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octan-2-yl)methanone, having the following structure:

or a pharmaceutically acceptable salt thereof. 